Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2016; 20: 4089-4111 Local bone marrow renin- system in the genesis of leukemia and other malignancies

I.C. HAZNEDAROGLU 1, U.Y. MALKAN 2

1Department of Hematology, Hacettepe University School of Medicine, Ankara, Turkey 2Department of Hematology, Hacettepe University School of Medicine, Ankara, Turkey

Abstract. – The existence of a local renin-an - Introduction giotensin system (RAS) specific to the hematopoietic bone marrow (BM) microenviron - The existence of a local renin-angiotensin sys - ment had been proposed two decades ago. Most of the RAS molecules including ACE, tem (RAS) specific to the hematopoietic bone ACE2, AGT, AGTR1, AGTR2, AKR1C4, AKR1D1, marrow (BM) microenvironment had been pro - ANPEP, ATP6AP2, CMA1, CPA3, CTSA, CTSD, posed by our group 1,2 . The major RAS molecules CTSG, CYP11A1, CYP11B1, CYP11B2, CYP17A1, including renin, angiotensinogen, angiotensin re - CYP21A2, DPP3, EGFR, ENPEP, GPER, ceptors , and angiotensin-converting HSD11B1, HSD11B2, IGF2R, KLK1, LNPEP, (ACEs ) have been detected at the BM microenvi - MAS1, MME, NR3C1, NR3C2, PREP, REN, RNPEP, 3 and THOP1 are locally present in the BM mi - ronment . Locally active BM RAS affects the im - croenvironment. Local BM RAS peptides control portant stages of physiological and pathological the hematopoietic niche, myelopoiesis, erythro - blood cell production via autocrine, paracrine, poiesis, thrombopoiesis and the development of and intracrine pathways 4,5 . Local BM RAS pep - other cellular lineages. Local BM RAS is impor - tides control the hematopoietic niche 6, tant in hematopoietic stem cell biology and mi - myelopoiesis 7, erythropoiesis 8, thrombopoiesis 9 croenvironment. Angiotensin II regulates the and the development of other cellular lineages 6,10- proliferation, differentiation, and engraftment of 12 4,5 hematopoietic stem cells. Activation of Mas re - . BM stromal niche contains local RAS , ceptor or ACE2 promotes proliferation of CD34+ which controls the important hematopoietic func - cells. BM contains a progenitor that expresses tions 3,13 . Furthermore , the BM stromal microen - renin throughout development. Angiotensin II at - vironment contains angiotensin type 1 and type 2 tenuates the migration and proliferation of receptors (AT1R and AT2R) and the inhibitory CD34+ Cells and promotes the adhesion of both MNCs and CD34+ cells. Renin cells in tetrapeptide N-Acetyl-Ser-Asp-Lys-Pro (AcSD - hematopoietic organs are precursor B cells. The KP). Ang-II is the main RAS effector mediator , renin cell requires RBP-J to differentiate. Mutant and it demonstrates its hematopoietic effects by renin-expressing hematopoietic precursors can stimulating angiotensin receptors , which are type cause leukemia. Deletion of RBP-J in the renin- 1 (AT1) and type 2 (AT2) receptors in the BM expressing progenitors enriches the precursor microenvironment 4,5 . ACE/CD143 degrades AcS - B-cell programme. Mutant cells undergo a DKP ; as a result , the recruitment of primitive neoplastic transformation, and mice develop a 9,14-17 highly penetrant B-cell leukemia with multi-or - stem cells into S-phase is triggered . More - gan infiltration and early death. Many biological over , Ang-II stimulates AT1/AT2 receptors, so conditions during the development and function that it has stimulatory/inhibitory effects on the of blood cells are mediated by RAS, such as JAK-STAT pathway , which is associated with apoptosis, cellular proliferation, intracellular sig - physiologic functions of erythropoietin, throm - naling, mobilization, angiogenesis, and fibrosis. bopoietin , and other hematopoietic cytokines The aim of this paper is to review recent devel - opments regarding the actions of local BM RAS throughout normal hematopoiesis and in myelo - in the genesis of leukemia and other malignan - proliferative diseases 9,18-20 . Local RAS is active cies molecules. even at the phase of primitive embryonic hematopoiesis 21-24 . Recent developments regard - Key Words: ing the actions of local bone marrow (BM) renin- Local bone marrow renin-angiotensin system, angiotensin system (RAS) in the genesis of Leukemia, Malignancies. leukemia are depicted in Table I .

Corresponding Author: Ibrahim C. Haznedaroglu, MD; e-mail: [email protected] 4089 I.C. Haznedaroglu, U.Y. Malkan

Table I. Recent developments regarding the actions of local bone marrow (BM) renin-angiotensin system (RAS) in the genesis of leukemia.

The findings Conclusions Perspectives Reference

Renin cells in hematopoietic BM contains a progenitor that Mutant cells undergo neoplastic 101. Belyea et al, organs are precursor B cells expresses renin throughout transformation, and mice develop Nat Commun development and possesses a highly penetrant B-cell leukemia 2014; 5: 3273 a B-lymphocyte pedigree with multi-organ infiltration and early death Renin cell requires RBP-J to Deletion of RBP-J in the renin- Mutant renin-expressing 101. Belyea et al, differentiate expressing progenitors hematopoietic precursors Nat Commun enriches the precursor B-cell can cause leukemia 2014; 5: 3273 gene programme and constrains lymphocyte differentiation. Deletion of RBP-J in renin- lineage cells leads to enhanced cell cycle progression and increased cell proliferation. A transcriptomic ACE, ACE2, AGT, AGTR1, There is a local RAS in the 52. Nehme et al, meta-analysis revealed the AGTR2, MAS1, REN, ANPEP BM affecting physiological and Sci Rep. 2015; 5: atlas of BM RAS and other critical molecules of neoplastic cellular proliferation 10035 RAS are locally present in the bone marrow Ang II attenuates migration Activation of Mas receptor or Local BM RAS is important in 77. Singh et al, Am J and proliferation of CD34+ ACE2 promotes proliferation hematopoietic stem cell biology Physiol Heart Circ Cells. Ang II promotes the of CD34+ cells and microenvironment hysiol 2015; 309: adhesion of both MNCs P H1697-H1707 and CD34+ cells Specific immunoreactive Renin-like activity Intracrine effects of renin is 44. Wulf et al, Br J renin-like peptide of 47 kDa converting angiotensinogen important in leukemogenesis Haematol 1998; 100: isolated from AML blast cells to angiotensin I in leukemic 335-337 blast cells Over expression of ACE Renin expression could Autocrine effects of RAS is 35. Aksu et al, Leuk surface antigen in leukemic have a role on the leukemia enhanced in leukemogenesis Lymphoma 2006; myeloid blast cells had development and 47: 891-896 been detected. angiotensin may act as an 36. Beyazıt et al, autocrine growth factor J Natl Med Ass for AML cells 2007; 99: 57-63 Chronic Ang II infusion Ang II accelerates HSC to Angiotensin II regulates the 157. Kim S et al, regulates HSC proliferation, myeloid differentiation and proliferation, differentiation, Hypertension. 2016; mediated by angiotensin Ang II impairs homing and and engraftment of 67: 574-584 receptor type 1a reconstitution potentials of hematopoietic stem cells the donor HSCs Angiotensin II utilizes JAK-STAT pathway serves as Local BM RAS is important in 20. Vrsalovic et al, the JAK-STAT pathway a point of crosstalk between the signal transduction of leukemia Cancer Biol Ther components of the locally 2007; 6: 1434-1436 present RAS in the bone marrow and hematopoiesis

Many biological conditions during the devel - Besides, corrupted apoptosis, weakening of cell opment and function of blood cells are mediated differentiation, uncontrolled signaling , and an - by RAS 25 , such as apoptosis 26 , cellular prolifera - giogenesis of cancer are the other factors that tion 27 , intracellular signaling 18,28 , mobilization 29 , have roles in the clonal tumoral disease mecha - angiogenesis 30 , fibrosis within the cytokine net - nism 34-39 . Many different pathological prolifera - work 31 , and many others 4,5,32,33 . Increased creation tive stages lead to the creation of neoplastic of neoplastic cells is the major characteristic fea - blood cells , which are derivative of leukemic ture of hematological clonal neoplastic diseases. stem cells. In the literature, it was stated that lo -

4090 Local bone marrow renin-angiotensin system in the genesis of leukemia and other malignancies cal BM RAS could play a role in the develop - The role of Ang-II in the proliferation of all lin - ment of neoplastic malignant blood cells 34-36,40-45 . eages in bone marrow was proved previously. Local RAS functions in primitive embryonic When Ang-II was given externally , the colony de - hematopoiesis confirm the hypothesis that local velopment from HSC to CFU-GM and CFU- autocrine BM RAS may play a role in neoplastic GEMM was enhanced 12 . TNF-alpha production is hematopoiesis 21-24 . managed by Ang-II as well as its secretion from The aim of this paper is to review recent de - bone marrow by the regulation the monocytic lin - velopments regarding the actions of local BM eages 53 . The function of Ang-II in the management RAS in the genesis of leukemia and other ma - of normal and non-functional hematopoiesis is not lignancies. The presence of renin 44 , ACE 35 , an - well understood. The study of Richmond et al 54 giotensin II (Ang-II) 46 , and angiotensinogen 36 has greatly contributed to the knowledge on this have already been proven in leukemic blast issue . In the BM microenvironment, secretion of cells. Besides, the formation of pathological tu - arachidonic acid is regulated by the local Ang-II. moral blood cells is affected by RAS-modulat - Arachidonic acid is secreted by the effect of Ang- ing agents 47 . The local BM RAS in leukemogen - II , and then it moves to a cellular section of BM. esis still needs to be clarified, and this issue is After then , arachidonic acid plays the role of a sig - the main research subject 4,5 . Currently, Phase nalling molecule ; thus , it regulates the production I/II clinical trials of a pharmaceutical agent of or inhibition of hematopoietic precursors. Arachi - peptide angiotensin 1-7 (Ang-1-7) have been donic acid is known to have eicosanoid metabo - conducted to evaluate the role of local BM RAS lites , and these two substances play important in different diseases 33,48,49 . roles in the regulation of hematopoietic pathways 54 . Local BM RAS has substantial effects The Local Bone Marrow on the hematopoietic mechanisms , especially on Renin-Angiotensin System myeloid and eritroid cells 1,4,5 . Local BM RAS and Hematopoiesis plays its role through the regulation of important Entire blood cells are derived from hematopoi - peptides , which controls hematopoiesis. With the etic BM , which is a very complex organic system. help of ACE, Ang I transforms to Ang II , while To preserve the management of hematopoietic cell bioactive SP, Ac-SDKP , and Ang 1-7 have been in - growth, the main important growth factors are activated by ACE. Furthermore, during this supplied by the local BM microenvironmental process , Substance P (SP) is secreted from nerve stromal cells that have contact with committed endings, which are launched against the BM mi - hematopoietic precursors and HSC. Cytokines and croenvironment. BM stromal and hematopoietic bioactive peptides are some examples of factors cells secrete RAS peptides by the AT1 and NK1 that control most of the processes in post-natal receptors that regulate the effect of Ang II and SP, hematopoiesis within the BM microenvironment. respectively (Figure 1). Also, it has been proven The BM hematopoietic system is regulated by the that the important receptor of Ang 1-7, MAS is local BM RAS in many different ways , such as present in BM stroma 12 . autocrine, paracrine, intracrine. It was shown pre - viously that the hematopoietic RAS regulates the RAS and Myelopoiesis evolution of blood cells 1,4,5 . CD34+ hematopoietic Local BM RAS contains ACE (CD143) , which cells contain Angiotensin II type 1a (AT1a) recep - has an important role in myelopoiesis. In a study tors that augment production of hematopoietic that was conducted by Lin et al 7, myelopoietic progenitors of BM and umbilical cord blood in disorders were shown to develop in ACE-knock - different clinical conditions 32 . ACE is a regulator out mice . These myelopoietic disorders include of hematopoiesis 7,15,21,50,51 . Entire RAS molecules augmented bone marrow myeloblasts, myeloid including ACE, ACE2, AGT, AGTR1, AGTR2, cells and amplified extramedullary myelopoiesis. AKR1C4, AKR1D1, ANPEP, ATP6AP2, CMA1, Myeloid differentiation and development increas - CPA3, CTSA, CTSD, CTSG, CYP11A1, es when AT1 receptor binds with Ang-II. The CYP11B1, CYP11B2, CYP17A1, CYP21A2, myelopoietic role of ACE and Ang-II was pre - DPP3, EGFR, ENPEP, GPER, HSD11B1, sented at the Hematopoietic Stem Cell (HSC) HSD11B2, IGF2R, KLK1, LNPEP, MAS1, level previously 7. Some leukocytes have the an - MME, NR3C1, NR3C2, PREP, REN, RNPEP, and giotensinogen gene ; moreover , they secrete an - THOP1 are locally present in the bone marrow , as giotensinogen. This finding also favors local represented by transcriptomic molecular studies 52 . RAS-modulating effects on myelopoiesis 55 .

4091 I.C. Haznedaroglu, U.Y. Malkan

4092 Local bone marrow renin-angiotensin system in the genesis of leukemia and other malignancies

Figure 1. The role of RAS in normal and leukemic hematopoiesis, as well as the plasticity and systemic circulation, are de - picted in Figure 1. BM local ACE controls peptides for hematopoiesis. Ang I, Ang II, Ac-SDKP, and Ang 1-7 are created in other tissues and transferred to the BM by circulation, and SP is secreted from the nerve ending projecting to the BM. ACE se - cretes Ang II from Ang I and reduces the bioactive SP, Ac-SDKP, and Ang 1-7. Both stromal cells and hematopoietic cells are equipped with AT1 and NK1 receptors and mediate the action of Ang II and SP, respectively. Mas, the receptor for Ang 1-7, can be detected in BM. These peptides thus can either directly stimulate hematopoietic cells or perform their actions through stromal cells. Local bone marrow RAS in association with the yolk sac embryonic hematopoiesis has a role in the develop - ment, creation, proliferation, and differentiation of the hematopoietic progenitors. The metabolic cascades of angiotensin pep - tides and corticoid and glucocorticoid pathways are shown using symbols of coding for the substrate, the enzymes, and the receptors involved in the pathway. Angiotensin peptides and steroid hormones are represented in gray using their usual ab - breviation. Normal B-cell development proceeds from hematopoietic stem cells (HSC) by multiple phases to eventually con - vert mature B cells. A small subset of pro-B cells express renin and are named BRenin-cells. In this model, stimulation of the renin promoter in BRenin-cells results in cre recombinase expression and subsequently RBP-J deletion. These cells fail to dif - ferentiate along the normal B-cell pathway and undergo epigenetic initiation and enrichment of a precursor B-cell gene pro - gramme. Mutant cells additionally experience cell cycle progression and cell proliferation, ultimately resulting in expansion of a lymphoblast population and the development of precursor B cell leukemia (Refs; 4,12,52,80,101). Abbreviations : HSPC: Hematopoietic stem/progenitor cells; ACE: Angiotensin converting enzyme; CML: Chronic myeloid leukemia; Ang: An - giotensinogen; CFU-GM/E: Colony forming units-Granulocyte-Macrophage/erythroid; JAS/STAT: Janus kinase/Signal trans - duction and transcription; BC: Blood cell; Ang: Angiotensin; Preg: Pregnanolone; Prog: Progesterone; DOC: deoxycortisol; 17-OHP: 17-OH Progesterone; ACE: angiotensin I converting enzyme; ACE2: angiotensin I converting enzyme type 2; AGTR1: angiotensin II type 1 receptor; AGTR2: angiotensin II type 2 receptor; AKRIC4: aldo-keto reductase family 1, mem - ber C4; AKRID1: aldo-keto reductase family 1, member D1; ANPEP: alanyl-; ATP6AP2: prorenin/renin recep - tor; CMA1: 1; CPA3: A3; CTSA: ; CTSD: cathepsin D; CTSG: ; CYP11A1: cytochrome P450, family 11, subfamily A, polypeptide 1; CYP11B1: cortisol synthase; CYP11B2: aldosterone synthase; CYP17A1: cytochrome P450, family 17, subfamily A, polypeptide 1; CYP21A2: cytochrome P450 enzyme, family 21, subfamily A, polypeptide 2; DPP3: dipeptidyl-peptidase 3; ENPEP: (aminopeptidase A); GR: glucocorticoid receptor; HSD11B1: hydroxysteroid (11-beta) dehydrogenase 1; HSD11B2: hydroxysteroid (11-beta) dehydro - genase 2; IGF2R: insulin-like growth factor 2 receptor; KLK1: tissue kallikrein; LNPEP: leucyl/cystinylaminopeptidase; MAS1: MAS1 proto-oncogene; MME: membrane metallo-; MR: mineralocorticoid receptor; NLN: neurolysin (metallopeptidase M3 family); PREP: prolyl endopeptidase; REN: renin; RNPEP: arginyl aminopeptidase (); THOP1: thimetoligopeptidase 1. Images of IGF2R36, ATP6AP237, MR38, GR39, G-protein coupled receptors (AGTR1, AGTR2, GPER and MAS1)40 and LNPEP41.

The role ACE in myelopoiesis was revealed by ly, local BM RAS modify the growth factors’ sig - Lin et al 7. They found that the quantities of neu - nals that are produced from the BM microenvi - trophils and erythroid cells are decreased by 37% ronment. in ACE-knockout mice. Furthermore , in ACE- In the BM, the negative physiological regula - knockout mice , some myeloid precursors like tor of hematopoiesis, N-acetyl seryl-aspartyl- myeloblasts, eosinophils, and immature myelo - lysyl-proline (AcSDKP) is inactivated by cytes increased by 2.2, 2.3, and 2.5 times, respec - ACE 15 . The increase in ACE effects results in a tively. Also , the nucleated erythroid precursors decrease of AcSDKP by increasing its transfor - were found to be reduced to 77 % from normal mation into an inactive form ; thus , the inhibitor standards ; as a result , anemia was observed in effects of proliferation on hematopoiesis dimin - these mice 7. The clinical course of the ACE- ish. AcSDKP inhibits the production of knockout mice worsens because of the hematopoietic progenitors and pluripotent HSCs splenomegaly which is caused by extramedullary by preventing them to enter the S phase of the hematopoiesis. Mice without ACE had 10 times cell cycle 14,16,34 . reduced Ang-II levels compared to wild mice. The function of AcSDKP in ACE activity and ACE and Ang-II play roles in myelopoiesis by ACE expression were investigated by Oliveira et increasing the central transcription factor, al 17 in murine BM. In a kinin B1 receptor knock - C/EBP 7. ACE-KO mice had reduced C/EBP in out (B1KO) mice model, a reduction in erythroid its macrophages ; however , this phenomenon can (Ter119+), granulocytic-macrophage (Gr1+/ be normalized by giving Ang-II 12 . It can be con - Mac1+), CD-220+, CD3+, and Lin-Sca1+c-Kit+ cluded that hematopoiesis is regulated by local (LSK) cells were observed under ACE hyper - BM RAS in two major ways. Firstly, local BM function. Also, in B1 receptor knockout mice RAS controls the internal signals of transcription with ACE hyperfunction, after injection of Abz- factors that change the gene expression. Second - YRK(Dnp)P-OH, B1KO LTBMC ACE activity

4093 I.C. Haznedaroglu, U.Y. Malkan was found to be increased compared to wild role of Ang-II in erythropoiesis 59,60 . Ang-II in - mice. The importance of these data is not yet creases erythropoiesis by increasing erythroid clarified 17 . progenitors 8,61-63 . Kato et al 8 suggested that per - Hematopoietic recovery following myelosup - sistent erythrocytosis develops in mice that have pression is increased by Angiotensin (1-7) (Ang both the human renin and angiotensinogen 1-7). Ang 1-7 can be produced from Ang-II or genes. On the other hand, in BM transplantation Ang-I with the help of ACE2. The BM microen - studies , AT1a receptors on BM-derived cells vironment includes Mas receptors, which regu - were shown to be unnecessary for RAS linked late the proliferative role of Ang 1-7 on HSCs 32 . erythrocytosis 8. Kaneko et al 61 found that in BM The therapeutic effect of Ang 1-7 on hematopoi - erythroid cells there are (Pro)renin receptors etic injury secondary to radiation after total body (PRRs ), and these PRRs are amplified by IFN- irradiation (TBI) has been investigated by gamma. So, IFN-gamma, an inflammatory cy - Rodgers et al 56 . In this study , subcutaneous injec - tokine seems to inhibit erythropoietin secretion tion of Ang 1-7 after TBI amended the survival and erythropoiesis. Erythroid cells contain PRR from 60% to 92-97%. Moreover, thrombocytope - freely from their differentiation phases. After nia frequency secondary to radiation was halved. (pro)renin binds PRR, mitogen-activated protein Furthermore, Ang 1-7 increased the proliferation kinase (MAPK) ERK1/2 signaling pathways are of various hematopoietic cells such as early stimulated 61 . As a result , local BM RAS controls mixed progenitors , erythroid progenitors , erythropoiesis by autocrine and intracrine ways. megakaryocytes and BM myeloid progenitors, The (pro)renin receptor has recently come out as approximately 4, 3.5, 2.5, and 4.5 folds , respec - part of the RAS 64 . The human renin/prorenin re - tively 56 . As a result, it is likely to name Ang 1-7 ceptor (RER) has been found in the intracellular as a pan-hematopoietic cytokine proliferative perinuclear zone. In addition, promyelocytic agent as it boosts many important phases in zinc finger protein (PLZF) , which is a transcrip - hematopoiesis and myelopoiesis 27,29,33,48,49,56,57 . So, tion factor , was recently acknowledged as a pro - nowadays many experimental studies are going tein interaction partner of the renin receptor. Af - to make an Ang 1-7 drug for the regulation of lo - ter renin binds to RER, PLZF moves from the cal BM RAS-mediated hematopoiesis in different cytoplasm to the nucleus, enabling positive or clinical situations 33,48,49 . The ACE2/Ang (1- negative control of target genes 65 . PLZF in 7)/Mas receptor-axis-oriented drugs are especial - CD34(+) cells and early erythropoiesis manages ly promising 32 . the c-kit expression transcriptionally 66 . Ang II - Another effect of Ang-II over BM AT1 recep - induced cellular effects through an AT2 recep - tors is the management of monocyte-lineage cells tor-dependent signaling pathway is controlled that implies proatherogenic effects in the cardiac by PLZF over AT2 receptor. The angiotensin II- microenvironment 53,58 . Macrophage growth re - AT2-PLZF-GATA4 signal contributes in the quires AT1 signaling. In a study which was con - control of Ang-II linked pathological changes 67 . ducted by Tsubakimoto et al 53 with BM chimeric However , these issues still need to be clarified apoE(-/-) mice re-populated with AT1-deficient by future experimental studies. Savary et al 68 (Agtr1(-/-)) or wild-type (Agtr1(+/+)) BM cells, proposed that the local RAS exists in a primi - Ang-II were found to control the c-Fms in HSCs tive embryonic erythropoiesis located in the and monocytic cells over BM stromal cell-de - yolk sac of the chicken embryo. Yolk sac endo - rived TNF-alpha in order to increase derm contains ACE, renin, angiotensinogen, and macrophage-colony-stimulating factor (M-CSF)- AT receptor alongside with the variation of induced management of monocytic cells. In this blood islands in the adjacent yolk sac meso - investigation , it was proposed that the M-CSF- derm. ACE and Ang-II receptor blockers were induced transformation from HSCs (c-Kit(+)Sca- found to reduce erythroblast production , which 1(+)Lin(-)) to promonocytes (CD11b(high)Ly- was stimulated by RAS. As a result, it can be 6G(low)) was decreased in HSCs from AT1-defi - concluded that the local autocrine RAS plays a cient Agtr1(-/-) mice 53 . role in the regulation of both primitive and de - finitive erythropoiesis. ACE inhibitors or an - RAS and Erythropoiesis giotensin receptor blockers decrease hematocrit It is known that ACE-knockout mice develop levels. The reason for this may be the RAS inac - anemia. The treatment of this anemia with an tivation by these drugs in the BM cellular au - injection of Ang-II is the evidence of the main tocrine RAS network 69 .

4094 Local bone marrow renin-angiotensin system in the genesis of leukemia and other malignancies

RAS also has a role in the regulation of patho - Jak2V617F mutation is inhibited by the AG - logical and neoplastic erythropoiesis. An - TRAP. The presence of AGTRAP over-sensitized giotensin II receptor type 1 in erythroid progeni - UT7/TPO cells and recombinant human tors was thought to play a role in the postrenal megakaryocyte growth and development factor transplant erythrocytosis 62 . It has also been sug - (rhMGDF) increases the proliferation of cells by gested that in BM of polycythemia verae (PV) , a little amount of rhMGDF 9. there are mRNAs that consist of augmented local Thrombotic and inflammatory effects develop production of the RAS elements. As a result in with the platelets that contain AT1 receptors 71 . PV, there is an increase in local BM RAS while Platelet production indicators and in vivo platelet BM CD143 receptors decrease 40 . activation are amplified by Ang-II 72 . When Ang- II was given, rolling thrombocytes, adhered RAS and Thrombopoiesis thrombocytes on the leukocytes and the endothe - AGTRAP (i.e., Angiotensin II Receptor-Asso - lial cells, rolling leukocytes, and adhered leuko - ciated Protein ) is an element of RAS systems that cytes , as well as an escalation in thrombocyte- plays a role in hematopoiesis . It also amplifies leukocyte-endothelial cell relations by means of the thrombopoietin receptor Mpl 9. Megakary - dose and time in the cerebral veins , were ob - ocyte growth and thrombocyte development are served 71 . mediated by the Mpl proto-oncogene. Also , Mpl proto-oncogene controls the HSC homeostasis RAS and Other Blood Cell Lineages: and self-renewal 70 . Furthermore, Mpl signaling is Dendritic Cell s, Mast Cells, T-lymphocytes, essential for HSC homeostasis. Retroviral inser - Monocytes, Macrophages, and Antigen- tional mutagenesis was achieved in a study by Presenting Cells Kwiatkowski et al 9. Kwiatkowski et al 9 conduct - There are many previous studies reporting that ed this study by an MSCV established vector local RAS plays a role in hematopoietic cell pro - coding for a drug dependent, dimerizable, fusion duction and development. Furthermore , local protein , which has the cytoplasmic part of Mpl. RAS is also involved in the development of anti - With the help of this vector, the gene arrange - gen presenting cells, T-lymphocytes, dendritic ment can be disturbed by insertion , and neigh - cells, mast cells, monocytes, and macrophages 4,5 . boring genes can be augmented by the intact long Cleavage of a C-terminal dipeptide or tripeptide terminal repeats of the vector. In another study, a is necessary for the degradation of substance P vector is used as a transducer of the human (SP) in the BM microenvironment, lymphoblasts, leukemia cell line K562 that contains all RAS and lymphocytes by ACE 12 . components 45 . Without Mpl signaling, the cell Antigen -presenting cells (APCs) have local perished after erythroid differentiation. RAS in the cellular part of the immuno-hemato - Mutations that are synergistic with Mpl signal - logical structure. T cells and APCs have AT1R 58 . ing are probably in cells that gain a proliferative Dendritic cells need the Ang-II type 1 receptor state and need Mpl function. Over-represented for their normal growth and functionality 73-75 . T clones are easily detected by cloning of retroviral cells are stimulated via dendritic cells that are fo - integration sites (RIS) from particular popula - cused APCs on this function. If Ang-II binds the tions. RIS indicates a gene that may cooperate AT1 receptor , dendritic cell production is aug - with Mpl. A RAS protein named Angiotensin II mented; however, Ang-II and AT2 receptor cre - Receptor-Associated Protein (AGTRAP) has ates inhibitory effects on this process 12,75 . been detected from these indicated genes 9. Nahmod et al 75 investigated the role of Ang II Kwiatkowski et al 9 tried to clarify the role of and AT1 and AT2 receptors in dendritic cell de - AGTRAP . They proposed that Mpl signal stimu - velopment . Dendritic cell development is sup - lates K562 cells , and AGTRAP is highly present pressed by pharmacologic inhibition of the AT1 in K562 cells. The high presence of AGTRAP receptor in a GM-CSF -amplified culture. As a re - expression in K562 cells results in an increase in sult , surface maturation indicators reduced, endo - K562 cells by reducing the doubling time. cytosis decreased , and allogeneic T cell produc - Mpl -dependent K562 cell production is ampli - tion suppressed. However, AT2 inhibition or Ang fied by Mpl signaling by AGTRAP. Mpl signal - II injection to culture had contrary function and ing and JAK2 is essential for Mpl dependent augments progenitors in gaining the role of the K562 cells that express AGTRAP. The prolifera - dendritic cells 75 . BM-derived dendritic cells with tion of HEL cells that have the homozygous a low level of AT1a secreted greater amounts of

4095 I.C. Haznedaroglu, U.Y. Malkan monocyte chemoattractant protein-1 74 . The pro - each different tissue. As a result, it can be con - duction of dendritic cells contains major modifi - cluded that in the near future , tissue -specific tar - cations in their features without AT1a and/or geted therapy may be possible. AT1b subtypes 73 . Dendritic cells are stimulated The immune system has a major role in the by Ang-II with autocrine and paracrine ways by pathogenesis of hypertension. T-lymphocytes , AT1 that results in sustaining the inflammatory which are based on the vasculature and renal sys - reactions 73 . tem , may augment elevated blood pressure if The role of RAS on dendritic cells and APCs these lymphocytes are activated and gain pro-in - has a part in the underlying mechanism for im - flammatory features. Elevated sympathetic nerve mune-inflammatory diseases. Stegbauer et al 58 activity and norepinephrine secretion is accused observed an increase in renin, ACE, and AT1R in to be the main reasons for the activation of the the immune system in the myelin-oligodendro - immune system in hypertension onset. On the cyte glycoprotein-induced experimental autoim - other hand, increased sympathetic activity is mune encephalomyelitis. Also , they detected an known to act as an immunosuppressor , and pa - increase in renin, ACE, and AT1R in the immune tients with hypertension have a vulnerability to system by quantitative RT-PCR method 58 . In the infections. As a result , it may be interpreted that course of inflammation , the local RAS is stimu - in hypertension , norepinephrine stimulates par - lated in the immune system. The local RAS con - ticular immune cells while inhibiting others. trols the APC populations and the chemokines by Ang -II controls the activation of T-lympho - AT1R through autocrine-paracrine-intracrine cytes ; thus , Ang -II actually regulates the immune pathways. The amounts of CD11b+ or CD11c+ system 76 . However , the exact mechanism of ac - APC in the immune system and the spinal cord tion remains unclear . For the present , it seems were decreased by the inhibition of AT1R. Also, that in the treatment of hypertension, targeting inhibition of AT1R damages the presence of the immune system , which is manipulated by the CCL2, CCL3, and CXCL10 as well as CCL2- sympathetic nervous system , will result in a de - stimulated APC 58 . crease in blood pressure as well as immunosup - Mast cells secrete an effective growth factor, pression unless specific treatment modalities are preformed Ang-II. Hara et al 10 proposed that the developed 76 . mast cells contain the pre-formed Ang-II and Both cardiovascular protective and deleterious RAS system . Calcitonin gene-related peptide arms of RAS modulate the vasoreparative func - (CGRP) controls the Ang-II in mast cells. CGRP tions of CD34 cells 77 . The ACE2/Ang-(1-7)/Mas has two main effects. Firstly, the secretion of axis stimulates vasoprotection-relevant effects of Ang-II is increased. Secondly , the amount of an - these cells. In contrast, the ACE/Ang II/AT1 axis giotensinogen mRNA in a human is either directly or indirectly attenuates CD34 cell augmented by CGRP. Neural activity controls functions. As a result, relative expression of the mast cells , which could be named mobile RAS. two axes of local RAS in CD34 cells can be a Secretion of Ang-II in the organs correlates with good measure of their vasoreparative effects. the amount of mast cells 10 . Along similar lines, an imbalance to the aug - mented expression of the ACE/Ang II/AT1 axis The Tissue Ras System in Other Organs would stimulate dysfunction of CD34 cells and The RAS system is present in several tissues can be a prognostic marker for an increased risk of the human body. Nehme et al 52 proposed pre - for the development of cardiovascular disease 77 . liminary atlas for the organization of RAAS The bone marrow has been shown to have across 23 different normal human tissues . The multiple roles in disease and tissue healing 78 . extended RAAS (extRAAS) system is defined as Bone marrow -derived stem cells have been re - a set of 37 genes encoding classical and novel vealed to maintain tumor development and RAAS participants , including glucocorticoids metastases by the release of mesenchymal stem and mineralocorticoids. MAS1, prorenin , and cells and endothelial progenitor cells. Bone mar - renin receptors , as well as LNPEP-IRAP , are row cells assist as the progenitor for end-organ found to be important factors in RAS system cells. Cardiac stem cells, which have important among different tissues. For example , MAS1 and potential to advance cardiac function, are replen - ACE2 were expressed in the kidney , whereas ished after myocardial injury over proliferation LNPEP-IRAP was not. This atlas has enabled us and release of bone marrow -derived stem cells. to understand the variability of RAS system for Genotypic or phenotypic differences in bone

4096 Local bone marrow renin-angiotensin system in the genesis of leukemia and other malignancies marrow stem cells can lead to the generation of RAS signaling changed the development of inflammatory cells with varied activity leading to primitive hematopoietic progenitors 21 . Zambidis altered end-organ function 78 . et al 24 found that the hemangioblast differentia - BM contributes to hypertension by increasing tion is controlled by RAS. The human heman - peripheral inflammatory cells and their extrava - gioblasts were found to contain AT1 and AT2 24 . sation into the brain. Minocycline is an effective Moreover, the transformation of heman - treatment to alter neurogenic elements of hyper - gioblasts to progenitors is associated with the tension. BM-derived cells are involved in neu - regulation of signals over major Ang-II– roinflammation, and targeting them may be an binding receptors, AT1 and AT2 24 . In this study , innovative strategy for neurogenic resistant hy - the primitive and definitive Yolk Sac (YS)-like pertension therapy 79 . hematopoiesis is stimulated by ACE that was Bone marrow-derived hematopoietic stem found on the hemangioblast surface. Embryon - cells (HSC) can show incredible differentiation ic hematopoiesis’ progenitors were detected by activity in numerous non-hematopoietic organs. ACE expression and growth and development This enigmatic procedure is named `stem cell of human embryonic hemangioblasts were con - plasticity’ (SCP). HSC may endorse structural trolled by RAS. The growth of human heman - and functional repair in several organs, such as gioblast colony is reduced by captopril because the heart, liver, brain, and skeletal muscle via the captopril decreases the ACE activity. Local SCP 80 . RAS function leads to the stimulation of human angio-hematopoiesis from an ACE-heman - Local Renin-Angiotensin System gioblastic precursor of embryonic and definitive in Primitive Embryonic Hematopoiesis hematopoiesis 24 . First multipotent, hematopoietic cells that con - Sinka et al 22 investigated the existence of ACE tain the stem cells of the fetal and postnatal blood in the earliest, pre-aorta-gonad-mesonephros elements develop in the human embryo. The um - (AGM) phases of human intraembryonic an - bilical cord blood (UCB), the fetal liver, embry - gio-hematopoiesis. In this research , in the ini - onic para-aortic splanchnopleura, hematopoietic tial phases of human development, the cells in the aorta gonad mesonephros (AGM) hematopoietic potential in the splanchnopleura area is the primitive hematopoietic cells through is limited to evolving CD34-ACE+ precursors. embryonic hematopoiesis 21 . Many studies con - ACE+CD34-CD45- mesodermal progenitors centrated on the ACE (CD143) together with the transferring from the splanchnopleura to the local RAS 21-24 and human embryonic HSCs 81 . ventral aorta augment the CD34+ intra -aortic The development and function of the hematopoi - hematopoietic clusters. The yolk sac, etic system are controlled by local RAS since splanchnopleura, aorta, fetal liver , and BM in embryogenesis 23 . A HSC indicator, which is a so - the human embryo are the hematopoietic tis - matic isoform of ACE (CD143) , is detected by sues that comprise ACE. ACE has important monoclonal antibody (mAb) BB9. BB9 has reac - ro les for the preservation of embryonic tivity with embryonic cells at all phases of hematopoiesis 22 . These findings correlate with hematopoietic ontogeny 21 . Common yolk sac-like the statement of BM as a local RAS 1,2 . Sinka et precursors such as ACE+CD45-CD34+/- cells al 22 detected the BM ACE presence in the long have the role of progenitor for endothelium, bones of human embryos and fetuses by flow primitive , and definitive human lympho- cytometry. They found that the ACE present at hematopoietic stem cells 24 . the surface of CD34+CD45- cells and of some Endothelial cells within the yolk sac, placen - CD34-CD45+ cells, which are the first en - ta , and aorta form the multilineage hematopoietic dothelial and hematopoietic (probably mono - stem cells (HSC) and progenitor cells throughout cyte-macrophage) cells, create the marrow cav - embryogenesis 82 . Jokubaitis et al 21 suggested that ity. CD34-CD45, which are early hematopoiet - ACE, as detected by mAb BB9, is an indicator of ic precursors , are identified by ACE. primitive hematopoietic cells at all phases in the Hematopoiesis present in the medulla ry cavity development of the hematopoietic system. In this at the phases after 14 weeks and ACE identi - study , it was found that during the formation of fies CD34+CD45- endothelial cells but also the human hematopoietic system, BB9/ACE CD45+CD34+ hematopoietic cells. At this was detected. Also , BB9 was detected in the so - phase, some ACE+ cells do not have CD34 and matic form of ACE. Moreover , disturbance of CD45, and they represent mesenchymal cells

4097 I.C. Haznedaroglu, U.Y. Malkan in the BM microenvironment. CD34+ACE+ Renin-Angiotensin System in cells are found in the fetal liver and BM long- the Basic Pathobiological Events term blood-founding cells 22 . of Carcinogenesis and Cancer The hematopoietic stem cell niche can help the Dysregulation in a complex series of neoplas - differentiation of hemangioblasts in YS or tic pathobiological actions leads to carcinogene - AGM 21-24 . The selection of development of he - sis. The associations of RAS in neoplasia sym - mangioblasts into either hematopoietic precur - bolize a model for improved understanding of the sors or vascular endothelial networks is decided place of local BM RAS in hematological tumoral by the antagonistic competition between AT2 and diseases. The complex pathological network of AT1 for Ang-II binding on developing heman - neoplasia includes the inequity between cellular gioblasts. In embryonic and definitive proliferation/differentiation and apoptosis related hematopoiesis , AT1/ AT2-controlled stem cell de - to the immunopathological modifications and the velopment may be a widespread phenomenon. As genomic dysregulation due to somatic and/or a result, in order to develop the multipotent germline mutations, neoplastic intracellular sig - hematopoietic precursors from embryonic HSC , nalling due to oncogenic autocrine-paracrine- the angiotensin receptor signaling may be manip - intracrine possessions, neoplastic angiogenesis, ulated. fibrosis in the neoplasia microenvironment, and The phrase “stem cell plasticity” represents pathological mobilization of neoplastic the hypotheses about local BM RAS and the cel - cells 50,85,86 . One of the critical elements in the tu - lular development function of HSCs 19 . Post-natal mor microenvironment is the local RAS , and it HSCs have marked ability for cellular differentia - has vital effects in cancer metabolism, survival, tion in different tissues. These HSC functions im - angiogenesis , and invasion processes 87 . itating primitive hematopoiesis are dependent on Local tissue RAS affects cancer development and responsive to the definite signals existing in and metastases in an autocrine and paracrine way the local tissue microenvironment. The RAS hy - by the modulation of many neoplastic events, pothesis has been suggested about HSC homing such as angiogenesis, apoptosis, cellular in - and stem cell plasticity to create cardiomyocytes crease, immune answers, cell signaling, and ex - in the cardiac microenvironment, with the source tracellular matrix development. The development of data regarding the local cardiac and BM and stimulation of tumoral cells are controlled by RAS 19 . Renewing myocardial tissue could use locally formed Ang-II in intrahepatic cholangio - monitoring roles on circulating or resident stem carcinoma tissues 88 . Possible management of the cells by the locally active RAS. Cardiac RAS local RAS with various enzymes, peptides , and and hematopoietic RAS could cooperate to sus - feedback mechanisms can even symbolize a tain tissue roles since local RASs exist in differ - treatment target for the clinical control of neopla - ent tissues 19 . On the other hand, there is no data sia 50,85,86 . to verify this hypothesis. The development and DNA damage with single and double strand differentiation of BM mesenchymal stem cells breaks are stimulated by Ang-II. The evidence into cardiomyocyte-like cells are stimulated by of AT1 mediated DNA injury has been shown in Ang-II and 5-azacytidine 83 . The hypotheses re - a study which proposes the AT1 receptor block - garding RAS and HSC plasticity in different tis - er candesartan avoids all kinds of damage due sues such as the heart, kidney, brain, muscle, to Ang-II 89 . The progression of pancreatic can - nerves, and pancreas are supported by clarifica - cer may be postponed by enalapril together with tion of the existence and function of angiotensin aspirin 90 . Moreover , the creation of invasive peptides in primitive hematopoiesis 21-24 . There is murine pancreatic cancer in a genetically engi - an association between angiotensin and transd - neered mouse cancer model can be somewhat ifferentiation of epithelial cells into fibroblasts. prevented by enalapril and aspirin 90 . Similarly, Kidney growth is also mediated by local embry - losartan increases the effectiveness of systemi - onic RAS. The renal capacity to create its blood cally administered nanotherapeutics to highly fi - cells concurrently with in situ blood vessel for - brotic solid neoplasias, such as pancreatic adeno - mation is pointed out by the course of hemovas - carcinomas 91 . culogenesis closely associated to the roles of the The future of RAS blockers in cancer treat - local RAS 84 . Additional studies shall concen - ment has been described in two directions 92 . As a trate on these hypotheses in different experi - first approach, protocols using these drugs as mental settings. chemo-prophylactic agents could be considered

4098 Local bone marrow renin-angiotensin system in the genesis of leukemia and other malignancies to reduce cancer rates. The limited efficacy of associated with AT1 signaling 86 . RAS has been long-term use to compensatory rises in renin of associated with the reduction of ERK signaling ACEIs and ARBs can be a limitation, where and the stimulation of cell death receptors that strategies such as the combination of RAS block - result in apoptosis. On the other hand, AT1 stim - ers with a renin inhibitor should be anticipated. ulates mitogenic signals together with MAPK or Despite the multiple limitations, chemopreven - PI3K pathways and results in the downstream tion is thought to be a realistic method for de - stimulation of transcription factors along with creasing the rate of cancer, and RAS blockers nuclear factor- κB (NF- κB), which is accountable constitute a great potential approach. Another di - for the production of different anti-apoptotic pro - rection can be the use of RAS blockers as coad - teins, such as BCL-XL, survivin , and BCL2 86 . juvant agents in cancer therapy; however, the While the role of RAS in the apoptotic course is side effects may be a major problem 92 . not similar, those pathobiological data associated with apoptosis highlight the effect of the local RAS and Apoptosis and Leukemia RAS in carcinogenesis. Whether neoplastic cells experience apoptosis Telmisartan, an angiotensin II receptor block - or survive in response to RAS activation was de - er , induces apoptosis in Adult T-cell leukemia cided by the biological actions of angiotensin re - cells 97 . Adult T-cell leukemia (ATL) is a T-cell ceptors, AT1 and AT2, and pathological changes malignancy that presents after human T-cell in their signaling 86 . There are contradictory stud - leukemia virus (HTLV-1) infection. The tran - ies regarding apoptosis and RAS associa - scription factor PPAR plays various roles in lipid tions 26,28,86 . Signaling over AT2 is always linked metabolism, immune response, cellular differen - to the increase of apoptosis; however , stimulation tiation , and apoptosis. Telmisartan is well known of AT1 by Ang-II in neoplastic cells can improve for its unique ability to activate PPAR . It is pro-survival anti-apoptotic signaling 93 . Different found that telmisartan also induces significant governing, biological, inflammatory, angiogenic, growth inhibition and apoptosis in leukemia cell proliferative , and apoptotic activities are created lines from ATL patients by caspase activation by AT1 signaling relating with AT2 and/or the (caspase-3, 8 , and 9) in leukemia cells. Also , MAS receptor. Over activity of the RAS axis telmisartan increases the LC3-II-enriched protein stimulates apoptosis in the cardiac microenviron - fraction, demonstrating autophagosome accumu - ment 93 . The effect of angiotensin receptor rela - lation. tions in cellular apoptosis have been investigated in cardiomyocytes 94 . Staining for Caspase-3, an RAS, Cellular Proliferation-Differentiation apoptotic indicator , showed that increased the ex - and Leukemia pression of AT1 , as well as AT2 , leads to car - The development of progenitor cells is stimu - diomyocyte apoptosis with a modifications in the lated by RAS. The cellular renin, the Ang-II se - expression of the apoptotic molecules annexin V, cretion, the presence of AT2 receptor , and a re - Bax , and Bcl2. AT1-related cardiomyocyte apop - duction in angiotensinogen and ACE expression tosis could be somewhat controlled by the in - are related to cellular development 98 . DNA cre - crease of endogenous AT2. AT2 over-expression ation can be stimulated by Ang-II over AT1 as related cardiomyocyte apoptosis by an increase well as the generation of superoxide and phos - of iNOS 94 . Ghrelin could have an antagonistic ef - phorylation of the important oncogenic signaling fect in Ang II-related cardiomyocyte apoptosis pathways JAK/STAT3 and p38 MAPK 99 . The by reducing AT1 receptor expression and hinder - AT2 receptor has an inhibitory effect on cellular ing the stimulation of the endoplasmic reticulum development 93 . Throughout tumor development, stress pathway 95 . In contrast , it was shown in angiotensin peptides have an effect in pathologi - mouse models that the RAS blockade normalized cal cellular development . Developmental nephrotic the ACE2 expression and urinary Ang processes and homeostasis are regulated by an - (1-7) levels, avoided tubular apoptosis, and de - giotensin-generating cascades. Stimulation of the creased pro-fibrotic and pro-apoptotic gene ex - up-regulated AT1 receptor by Ang-II leads to the pression 96 . RAS signaling has been associated proliferation of breast cancer 100 . The promotional with improved survival and augmented prolifera - roles of Ang-II on cancer development are reliant tion of tumor cells. Apoptosis -increasing effects on modifications in cell cycle machinery and of the RAS are controlled by AT2 or the MAS re - downstream AT1 signaling actions. Stimulation ceptor; however , apoptosis -reducing effects are of the Ras-Raf-MAPK pathway and the tran -

4099 I.C. Haznedaroglu, U.Y. Malkan scription factors NF-kappaB and CREB takes on II-related phospho-ERK1/2 signaling pathway. a role in tumor cellular development amplified by Peptides that were intended to inhibit the AT1- Ang-II. AT1 blockers (ARBs) could inhibit the GABARAP relationship efficiently decrease in - proliferative roles of angiotensin peptides. Acti - tracellular gathering of AT1 and receptor gather - vated AT1R in AT1R(+)-MCF-7 breast cancer ing, cell surface expression , and signaling 103 . cells in vitro controls p53, PCNA , and cyclin D1 , Similarly, the biological actions of the en - which are also modified by Irbesartan 100 . dogenous RAS peptide, Ang (1-7) , are con - Bone marrow contains a progenitor that ex - trolled by suppression of the PI3K/Akt, P38 , presses renin throughout development and pos - and JNK signaling pathways 87 . Ang (1-7) and its sesses a B-lymphocyte pedigree that needs RBP- receptor Mas inhibits proliferation. Ang (1-7) J to differentiate 101 . The precursor B-cell gene suppresses both the development of human lung programme is enriched , and lymphocyte differen - neoplastic cells in vitro and cancer angiogenesis tiation is constrained by the deletion of RBP-J in in vivo over stimulation of the Mas receptor. renin-expressing progenitors. This process is fa - Ang (1-7) has an inhibitory role on metastasis, cilitated by H3K4me3 -activating marks in genes migration , and invasion in A549 human lung that control the pre-B stage. As a result, neoplas - adenocarcinoma cells 87 . Also, Ang (1-7) takes tic transformation occurs in mutant cells , and part in the mobilization of hematopoietic highly penetrant B-cell leukemia with multi-or - cells 29,32 . Notably, Ang (1-7) has dual effects. gan infiltration develops , which results in death. Although Ang 1-7 inhibits the development of neoplastic cells, it stimulates the mobilization of RAS and Intracellular Signaling hematopoietic cells. Ang (1-7) augments and Leukemia hematopoietic recovery after radiation therapy. An intracellular system is present in local tis - Also , angiotensin peptides stimulate hematopoi - sue RAS , which takes part in cell signaling and etic recovery after myelosuppression 48,49,104 . The function. Intracellular or nuclear RAS could have myelosuppressive treatments assessed included a significant effect in the pathobiology of RAS. total body irradiation and intravenous adminis - The G-protein and the non-G protein associated tration of two dissimilar chemotherapeutic signaling pathways can be stimulated by Ang-II drugs. The rises were most reflective and with AT1 receptors. Local intracellular RAS re - longest lasting in the bone marrow, similar to quires different signaling pathways , such as the detected roles on early progenitors and ef - MAPK kinases (ERK 1/2, JNK, p38MAPK), re - fects on blood cell lineages, counting detected ceptor tyrosine kinases (PDGF, EGFR, IRS-1), rises in red blood cell (BFU-E) and platelet and non-tyrosine receptor kinases (Src, (CFU-Meg) progenitors after Ang (1-7) therapy . JAK/STAT, FAK). Focal adhesion and extracellu - Furthermore, Ang-(1-7) increases dendritic cell lar matrix development are related with scaffold - functions and takes a part in the development of ing proteins, such as paxillin, talin, and p130Cas , human dendritic cells 48,49 . The mechanism for which are increased by Ang-II. These signaling the opposing cellular roles of Ang (1-7) is un - cascades cause cellular development, cell move - clear , but Ang (1-7) modifies the balance and ment, and disease advancement 28 . The JAK- concentration among proliferative and anti-pro - STAT pathway, a significant intracellular sig - liferative prostaglandins 105 . Since Ang-II also nalling system for many hematopoietic growth uses eicosanoid pathways, the inconsistent cel - factors, functions as a bridge between the ele - lular actions could be attributed to the dual roles ments of the local RAS in the bone marrow and on prostanoids. neoplastic hematopoietic diseases 18,20,53 . Intracel - The (pro)renin receptor ((P)RR) signaling is lular presence of all angiotensin receptor sub - elaborate in many pathophysiologies , ranging types is obvious in the nuclear compartment 102,103 . from cardiorenal end-organ damage to tumorige - The AT1 receptor is tied to the group of reactive nesis. The transcription factor promyelocytic oxygen species (ROS) over the stimulation of leukemia zinc finger (PLZF) is an adaptor pro - phosphoinositol-3 kinase signaling ; however , the tein of the (P)RR. (P)RR functions are mediated AT2 and Ang 1-7 receptors augment nitric oxide by its transmembrane and intracellular fragment (NO) generation 102 . The gamma-aminobutyric that has a role as an accessory protein of V-AT - acid (GABA) receptor-associated protein Pases. In a recent study , (P)R s signal transduc - (GABARAP) is related to the AT1a receptor. tion pathways have been shown to have roles in GABARAP increases the stimulation of the Ang- cardiovascular problems and tumorigenesis 106 .

4100 Local bone marrow renin-angiotensin system in the genesis of leukemia and other malignancies

In the literature , the new role of RAS has been somatic mutations that result with local RAS stated, in particular , Ang II distinct from other dysregulation could stimulate neoplastic develop - mutual functions, by considering its managing ment in solid tumors , such as breast, lung , and effect on the various signaling pathways involved gastric cancer 86,114-116 . AT1 and AT2 are present in the cardiac and endothelial tissue as well as in locally in gastric tumor and the mixture of AT1 stem cell transplantation 107 . Stem cell therapy has and ACE I/D gene polymorphism have an associ - been effective in avoiding and handling many ation with a nodal spread in intestinal type gas - diseases, including CVDs with a promising fu - tric tumors 117 . The DD genotype of ACE leads to ture 107 . an increased risk of squamous cell lung carcino - ma 118 . Ang-II could stimulate cancer cell extrava - RAS and Other Essential Pathobiological sation and metastasis 119 . The number of mice Events of Oncogenesis: Angiogenesis, with metastases and the number and size of Inflammation, Genomic Aberrations, and metastases per mouse were stimulated with the Immunological Dysregulation pre-treatment of cancer cells with Ang-II. In Angiogenesis has a an important role in car - vitro , angiotensin II stimulates the cancer cell ad - cinogenesis. Neoplastic angiogenesis is stimulat - hesion to endothelial cells, trans-endothelial im - ed by local RAS. Vascular endothelial growth migration and tumor cell relocation across the factor (VEGF) increases the pathological angio - extracellular matrix , thus expanding tumor genesis , and Ang-II stimulates VEGF 108 . Be - metastasis. A total of 102 genes differentially ex - nazepril has been shown to decrease the develop - pressed after Ang-II pre-treatment were detected ment of esophageal carcinoma xenografts. This by comparative DNA microarray 119 . Ang-II con - effect has been shown to be created by the reduc - trols two groups of connected genes associated tion of VEGF by benazepril , which eventually with its precursor angiotensinogen. Between leads to inhibition of neoplastic angiogenesis. those genes, the stimulated MMP2/MMP9 and Similarly, the inhibition of the RAS by ACE in - ICAM1 are the most important ones that are in - hibitors or ARBs noticeably decreased hepatocel - volved in cell adhesion, migration , and inva - lular carcinoma (HCC) in addition to a reduction sion 119 . of angiogenesis 109 . Also, in breast cancer and oth - Immunological dysregulation may lead to can - er tumors , the relationship between RAS and tu - cer development and progression. T and NK cells mor angiogenesis has been detected 85,108,110,111 . have the ability of secreting and delivering Ang - Ang-II escalates vascular permeability by secret - II to tissues since they have local RAS ele - ing prostaglandins and the vascular endothelial ments 120 . By using the mRNA analysis , NK and cell growth factor or the reorganization of cy - T cells were shown to have renin, renin receptor, toskeletal proteins 112 . Therefore , Ang-II has a angiotensinogen, and angiotensin-converting en - major role in the cancer -related inflammatory zyme. The co-stimulatory role of Ang-II and an - process, cell growth , and matrix production. ti-CD3-induced T and NK cell development with Moreover, Ang-II may have a role in the enroll - Ang-II therapy were detected. AT1 and AT2 were ment of inflammatory cells into the cancer tissue present in monocytes, NK , and T cells. These re - over the management of adhesion molecules and ceptors were effective in immunological actions , chemokines by resident cells. RAS stimulates the such as calcium signaling, chemotaxis, and de - NF-kappaB and AP-1 , which leads to the im - velopment 120 . Ang-II manages dendritic cell dif - munologically-induced inflammation and tran - ferentiation 75 . Decreased functions of dendritic scriptional regulation 86,112 . cells lacking in AT1 receptors have been The effect of ACE gene polymorphism on gas - detected 73 . AT1 receptors regulate the differentia - tric cancer development has been investigated 113 . tion and functions of dendritic cells and have a ACE is present locally in the gastric tumor , and critical role in cellular immune actions where lo - its gene polymorphism is related with metastasis. cal angiotensinergic systems are stimulated. ACE genotypes are related to the metastases of Bernstein et al 121 demonstrated a unique lymph nodes and the Union for International mouse model called ACE 10/10, presented high Cancer Control (UICC) tumor stage. In that ACE in macrophages ; however , ACE was miss - study, a few lymph node metastases and smaller ing from the blood vessels and kidney. It was de - UICC tumor stages (p = 0.01) were observed in tected that ACE 10/10 mice have a noticeable re - gastric tumor patients with the II genotype than sistance to the development of an aggressive and patients with the DD genotype 113 . Germline and usually used cancer model, B16 melanoma. ACE

4101 I.C. Haznedaroglu, U.Y. Malkan

10/10 mice reply to melanoma with a boosted in - renin-positive cases at diagnosis have no expres - flammatory answer, counting augmented cancer- sion throughout complete remission (CR) ; how - specific CD8+T cells. B16 tumor resistance is ever, the expression returned in relapse and per - transferred directly with macrophages or the en - sistent cases, when the disease was refractory to graftment of wild-type mice with ACE 10/10 therapy 42 . In AML and myelodysplastic syn - bone marrow 121 . ACE is the main peptidase that dromes, many different NUP98 fusions were de - is involved in MHC class I antigen processing 121 . tected , and the chimeric protein NUP98-HOXA9 Moreover , ACE expression is increased with anti - was one of them. Primary human CD34+ gen presenting cell (APC) development, ACE hematopoietic cells are managed by NUP98- controls surface MHC class I expression, ACE HOXA9 in terms of differentiation, proliferation, manages the MHC class I peptide repertoire, and gene expression. NUP98-HOXA9 may in - ACE edits self-antigens, ACE controls the exhi - crease the numbers of erythroid precursors and bition of viral antigens, and ACE acts as a car - harm myeloid and erythroid development . Aug - boxyl on proteasome products, and mented renin gene activity was observed during therefore, ACE reduction or ACE over-expression NUP98-HOXA9 boosted blast development 125,126 . affects immunogenicity 122 . The (pro)renin receptor [(P)RR] is very impor - tant in the RAS system since it has important functions in cardio-renal pathophysiology. (P)RR The Local Bone Marrow has angiotensin II-dependent and angiotensin II- Renin-Angiotensin System in independent effects. The catalytic activity of Neoplastic Hematopoiesis prorenin increases 5 -fold when renin binds to (P)RR. The (P)RR cooperates with promyelocyt - Renin and Leukemia ic leukemia zinc finger protein (PLZF) and Wnt The significance of renin presence as an ab - receptors and domains of the (P)RR are vital for normal leukemic indicator in acute leukemia has V-ATPase activity. High glucose induces (P)RR been detected by real-time PCR tests. Renin-like signal transduction ; however , deglycosylation of enzyme action changing angiotensinogen to an - prorenin eliminates its intrinsic effect in neuronal giotensin I has been identified in leukemic blast and epithelial cells 127 . In a study, the PLZF cells 44,123,124 . A definite immunoreactive renin-like translocation blocker genistein and the specific peptide of 47 kDa was obtained from acute V-ATPase inhibitor bafilomycin is used to sepa - myeloid leukemia (AML) blast cells. Renin is rate three distinct sub-pathways downstream of present in certain myeloid human leukemia cell the (P)RR 127 . The V-ATPase is associated with lines , such as K562, KU812 , and MEG-01 41 . The robust pro-proliferative effects, but prorenin renin system is detected in the in vitro model of causes moderate proliferation in vitro . On the the K562 leukemic cell line. Renin, an - other hand, PLZF does not affect cell number. giotensinogen , and ACE are detected in multipo - RAS in bone marrow is suggested to increase tential, hematopoietic neoplastic K562 leukemic cellular proliferation and differentiation. Renin in blast cells 45 . Renin expression was still present myeloid blast cells’ cytosol has been demonstrat - when K562 cells were put in the stimulators of ed , and some blast cells from some types of growth inhibition and/or differentiation . There - AML have also expressed renin. 77 % of AML fore, renin expression is related with a blastic and 100 % of ALL patients were detected as renin phenotype rather than with cell development 41 . positive in a previous study 128 . Renin expression Casares et al 41 suggested that renin is present in disappeared with hematological remission and some myeloid blasts ; however , normal BM does returned with relapse 129 . ACE inhibitors and the not have this expression . In this study , renin ex - AT1 receptor antagonist exert an antiproliferative pression was detected in cells from AML, chron - and apoptotic activity on leukemic cells 129 . ic myeloid leukemia (CML) , and acute lymphoid leukemia (ALL). The highest renin presence was Angiotensin Converting Enzyme (ACE) detected in AML cases , which was approximate - and Leukemia ly 47.2% of the cases. After the complete remis - The existence of ACE in hematopoietic stem sion of AML, renin presence was gone 41 . Inigo et cells during hematopoietic ontogeny shows that al 42 investigated 76 samples from AML cases, embryonic hematopoiesis 21-24 characterizes the with follow-up of positive cases. At diagnosis, effect of the ACE in neoplastic hematological renin was present in thirty-one cases (41%). All diseases , including neoplastic hematopoiesis.

4102 Local bone marrow renin-angiotensin system in the genesis of leukemia and other malignancies

The presence of ACE in human embryonic lym - found be increased 40 . The angiotensinogen gene phohematopoietic cells, an embryonic, fetal , and is present in leukocytes that are producing and adult hematopoietic tissue 21-24 , shows the role of secreting angiotensinogen, with the capacity of RAS on neoplastic tissues. Immunohistochemi - producing angiotensin 55 . CML cases had in - cal investigations have revealed the potential ef - creased ACE, angiotensinogen , and renin mRNA fect of ACE/RAS in BM by assessing ACE pres - levels , which are reduced after the administration ence in normal BM, several myeloproliferative of imatinib. The presence of RAS elements was diseases , and myelodysplasia 51 . ACE and p53 investigated in cases with CML at diagnosis and presence were observed in CD34+cells in cases at 3, 6 , and 12 months after diagnosis by quanti - with acute leukemia throughout and after induc - tative real-time PCR. After taking imatinib, ACE, tion therapy 43 . ACE presence in macrophages in angiotensinogen , and renin , mRNA levels are re - lymph nodes of Hodgkin lymphoma has been ob - duced in CML cases that are elevated before drug served 130 , and the role of ACE was also related administration. The RAS effects were expressive - with multiple myeloma 131,132 . ACE over-function ly varied between Sokal risk groups of CML, un - results in quicker hydrolysis of the AcSDKP pep - derlining the changed biological effect of RAS in tide that reduces in BM tissues, enabling HSC to cancer. Thus, the hematopoietic RAS has a role go in the S phase of the cell cycle 4,16,34 . ACE con - in neoplastic cell creation that may be able to be trols the serum concentration of AcSDKP , which changed by tyrosine kinase inhibitors , such as is a negative controller of the development of imatinib mesylate 137 . normal hematopoietic stem cells 14-16,133 . In vitro incubation of AML cells with an ACE inhibitor Angiotensin Peptides and Leukemia inhibits the development and colony-forming Human CD34+CD38- cells, CD34+CD38+ skill of AML cells. When Ang-II peptide added cells, lymphocytes, and stromal cells contain to AML cells, the colony-forming skills of those AT1a receptors. Ang-II is the major effector pep - cells are decreased 133 . A high presence of ACE tide of RAS , and it stimulates the angiotensin (CD 143) surface antigen in leukemic myeloid type 1a (AT1a) receptors exist on CD34+ blast cells has been observed with flow cytomet - hematopoietic stem cells ; as a result , hematopoi - ric tests. Furthermore, a positive association has etic progenitor cell development is increased 27 . been detected among ACE and bone marrow JAK-STAT is managed by Ang-II 18 . Angiotensin blast count 35 . ACE insertion/deletion (I/D) gene (1-7) also has a role in hematopoietic cell devel - polymorphisms in cases with hematological ma - opment 48,49,56,57 . Ang-II stimulates erythroid dif - lignancies were investigated together with acute ferentiation in the BM with AT1 receptors 63 . and chronic leukemia, myelodysplastic syn - Ang-II was detected as an autocrine growth fac - drome , and multiple myeloma 134 . In that study , tor for AML 46 . The RAS member AGTRAP is 80.4% of the cases had an ID/II genotype versus significant in hematopoietic cell development 55.9% in the control group, and there were 3.2 and existence and has a synergistic role with the times increased disease risk in the existence of development stimulating role of thrombopoietin the insertion allele (ID/II) 134 . receptor Mpl 9. BM AT1r levels in myeloma cases The role of the ACE I/D gene polymorphism presented a positive association with their BM were investigated in 108 PV and essential throm - infiltration pattern and tumor load, as detected bocytosis (ET) patients who were positive for the with beta-2 microglobulin 132 . AT1aR in BM have JAK2V617F mutation 135 . It was found that the an in -atherosclerosis development , as detected by ACE II genotype and I allele could be associated testing various BM chimeric mice that have BM with increased risk of ET and PV. On the other cells that were positive or negative for AT1aR. hand , the DD genotype and D allele could be as - The presence of AT1aR on BM-derived cells sociated with decreased risk of ET and PV. This could affect atherosclerosis by stimulating the in - study also revealed that the ACE I/D gene poly - filtration of BM-linked inflammatory cells in the morphism was independent of thrombosis. vessel wall. Inhibition of AT1R was not only in vascular cells. Also , in BM , this may be a signifi - Angiotensinogen and Leukemia cant strategy to avoid progression and destabi - Renin, angiotensinogen, and ACE mRNAs lization of atherosclerotic plaques. As a result, lo - were found to be present in human umbilical cal RAS has a role in the development of athero - cord blood cells 136 . In PV, the presence of an - sclerosis to provide very significant signs to bet - giotensinogen, ACE, and renin mRNA were ter understand the roles of the local hematopoiet -

4103 I.C. Haznedaroglu, U.Y. Malkan ic RAS on the growth of cancer 53,138-146 . The AcSDKP acts as a blocker of embryonic equivalent role of local RASs over the human hematopoietic cell development and stimulates body (including the myocardium, pancreas, pitu - angiogenesis in BM stroma. As a result, itary gland, ovary, and kidney) in health and dis - Goralatide (tetrapeptide Acetyl-N-Ser-Asp-Lys- eases characterize the correct source for the plan Pro) may be proposed as a probable treatment of future experimental investigation that tests this method in many different phases of hypothesis 4. hematopoiesis 155 . The new agent of angiotensin AT2R is involved in pancreatic cancer 147 . The 1-7 (Ang-1-7) is by now in Phase I/II clinical examination of pancreatic ductal adenocarcino - studies for the control of BM RAS in different ma (PDAC) species by immunohistochemical diseases 33,48,49 . However, since the main roles of analysis revealed that a relatively strong AT1R the local RAS are in an autocrine, paracrine , and expression was detected consistently in both nor - intracrine manner, future agents proposed to con - mal pancreas and PDAC areas, whereas moderate trol local RAS roles should be organized to have AT2R expression was detected in 78.5 % of a local targeted roles in the tissue microenviron - PDAC specimens and 100 % of the normal area ment, such as the BM. For example, Kawabata et of the pancreas. AT1R mRNA levels were con - al 156 developed a nanoparticle vector to influence siderably higher in the PDAC area than in the the efficacy of this cell-penetrating method for normal pancreas ; however , there is no such rela - tumor-aimed gene transfer in the setting of intra - tionship in AT2R mRNA levels. AT2R mRNA tracheal application. In the study, they showed levels had a negative correlation with overall sur - that the bolus application of dTAT NP-encapsu - vival. These advances may enable a novel AT2R lated angiotensin II type 2receptor (AT2R) or agonist to serve as an important therapeutic for TNF-associated apoptosis-stimulating ligand PDAC therapy in future. (TRAIL) cDNA evidently decreased cancer de - Angiotensin II-linked inflammatory pathways velopment. As a result, in that study , a unique were up-regulated in many organ systems by gam - gene transfer system was proposed that enables ma radiation. Wang et al 148 showed that ACE in - an active intratracheal method for lung cancer hibitors and ARBs can reduce radiation -linked in - gene treatment 155 . Kim et al 157 further highlighted juries in animal models that are exposed to gamma the important regulatory roles of Ang II on HSC radiation . Also , an active angiotensin peptide proliferation, differentiation, and engraftment. DAA-I (des-aspartate-angiotensin I) was found to Chronic Ang II infusion regulates HSC prolifera - attenuate the deleterious actions of angiotensin tion, mediated by angiotensin receptor type 1a, II 148 . It acts as an agonist on the angiotensin AT1 Ang II accelerates HSC to myeloid differentia - receptor and produces responses that oppose those tion and Ang II impairs homing and reconstitu - of angiotensin II. Radioprotection was facilitated tion potentials of the donor HSCs 157 . Besides the via the angiotensin AT1 receptor 148 . Moreover , the already known effects of RAS 158 , future investi - radioprotection linked with an increase in circulat - gational and clinical trials are thus required to ing PGE2, and this finding proposes that PGE2 explain the puzzling roles of local tissue RASs, elaborates with the radioprotection in DAA-I- including local BM RAS. These actions must treated mice. concentrate on separating local RAS connections with the complex pathobiological features of Future Perspectives cancer and on influencing autocrine-paracrine- Local tissue RAS, counting local hematopoiet - intracrine systems for the improved clinical han - ic BM RAS 4, is dynamic from embryogenesis 22 dling of neoplastic cases. to adult ages 149 . As a result, understanding the roles of local RAS can characterize an important –––––––––––––––– –-– –– treatment choice for controlling cancer 150 . The Conflict of Interest present medical application contains RAS-man - The authors declare that there is no conflict of interest re - aging agents for the management of cardiovascu - garding the publication of this article . lar diseases. The roles of RAS inhibitors on cir - culating RAS are identified; however , their roles References in the origin and development of cancer are still 50,151-154 unclear . Future treatment methods for the 1) HAZNEDAROGLU IC, T UNCER S, G URSOY M. A local modification of local BM RAS may concentrate renin-angiotensin system in the bone marrow. on locally active molecules. The tetrapeptide Med Hypotheses 1996; 46: 507-510.

4104 Local bone marrow renin-angiotensin system in the genesis of leukemia and other malignancies

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