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Molecular Biology of Polycythemias Josef T REVIEW ARTICLE Molecular Biology of Polycythemias Josef T. Prchal Overview EPO, O2-sensing, and hypoxia-inducible factor Under normal conditions, EPOproduction is mediated ei- Polycythemia is literally translated as "many cells in the ther by reduced red blood cell mass (anemia) or decreased O2 blood". Only erythrocytosis (an alternative term for these saturation of red cell hemoglobin (hypoxemia). Hypoxic stimu- disorders) produces polycythemia since leukocytes and lation results in increased production of hypoxia inducible factor platelets are present in blood in far smaller proportions. (HIF-1), which is the major factor for transcriptional activa- Polycythemia maybe due to increased proliferation or de- tion of the EPOgene (4). HIF-1 is also found in cells that do creased apoptosis of erythroid progenitors, or to delayed not express EPO,suggesting that HIF-1 is part of a widespread erythroid differentiation with an increased number of pro- O2-sensing mechanism providing transcriptional regulation of genitor cell divisions. Prolonged red cell survival, another vascular endothelial growth factor, glycolytic enzymes, and theoretical cause of polycythemia, has not yet been de- other genes (5-8). The identity of the O2 sensor and the mecha- scribed and with intact regulatory mechanismsis unlikely nism by which it regulates HIF-1 are unknownat the present to occur. Primary polycythemiasresult fromabnormali- time. Overall, HIF-1 is a physiologic regulator of genes that ties expressed in hematopoietic progenitors. In contrast, promote cell survival under ischemia and are expressed in re- circulating factors cause secondary polycythemia (1). There sponse to decreased cellular O2 tension (9). HIF-1 which regu- are acquired and congenital causes of both primary and lates vasculogenesis, is required for proper embryonic devel- secondary polycythemia (1). opment, and also plays an important role in carcinogenesis ( 10- (Internal Medicine 40: 681-687, 2001) 1 3). Thus, polycythemia maybe only one phenotypic manifes- tation of a congenital defect of the HIF-1 pathway (13). HIF-1 is composed of two subunits, HIF-1a and HIF-p (an Key words: erythrocytosis, hypoxia inducible factor (HIF), ARTN-like homologue) that form a heterodimer ( 14); only HIF- erythropoietin, hematopoiesis la is regulated by hypoxia. HIF-1a mRNAand protein levels are induced by hypoxia and decay rapidly with return to normoxia. Normoxia-induced ubiquitin-mediated degradation of the HIF-loc protein is the major regulator of HIF-la levels Regulation of Erythropoiesis: Relevance to (8, 15). Von Hippel Lindau (VHL) syndrome is a genetic ab- Polycythemic Disorders normality of this post-translational control. The mutated VHL protein targets HIF for oxygen-dependent proteolysis ( 16, 17), Erythropoiesis is the physiological process of the produc- mediated by a complexmechanismthat involves an interac- tion and renewal of the red blood cell mass. This process is tion of p subunit ofVHLprotein with other proteins (18, 19). influenced by a numberof hormones, receptors and transcrip- VonHippel Lindau syndrome is characterized by a high pro- tion factors (2). The principal hormone that regulates erythro- pensity for development of renal tumors; polycythemia occurs poiesis is erythropoietin (EPO). In adults, the kidney is the main but is not common.However, hemangioblastomas of the cen- source of EPO. After erythroid commitment, erythroid progeni- tral nervous system have long been associated with secondary tors express their ownEPO(3). In vitro studies have shown polycythemia and these tumors and elevated EPOare some- that variable levels of EPOare required at various stages of times seen with VHLdisease. erythroid maturation (2). Instead of EPO, pluripotent stem cells and primitive erythroid progenitors, i.e. early burst-forming Erythropoietin receptor units-erythroid (BFU-E), require stem cell factor, granulocyte- The interaction of EPO with the EPO receptor (EPOR) leads macrophage colony-stimulating factor (GM-CSF), and/or to homodimerizationand signal transduction that results in a) interleukin 3 (IL-3), and thrombopoietin for growth (2). stimulation of mitogenicity of erythroid progenitor cells, b) erythroid differentiation by induction of erythroid-specific ex- From the Division of Hematology/Oncology, Baylor College of Medicine, Houston, Texas Reprint requests should be addressed to Dr. Josef T. Prchal, Division of Hematology/Oncology Baylor College of Medicine, 1 Baylor Plaza 802E, Houston, Texas, 77030,USA Internal Medicine Vol. 40, No. 8 (August 2001) 681 Prchal pression of proteins such as globins, glycophorins, spectrin and ing signaling molecules resulting in "receptor cross-talk". This ankyrin, and c) prevention of apoptosis of erythroid progeni- complexinteraction of serum factors, receptors, and post-re- tors (20, 21). The cytoplasmic portion of EPORcontains a posi- ceptor signaling molecules capable of fine control may not be tive growth-regulatory domain that interacts with Janus 2 ty- emulated by in vitro experiments using cell lines, artificial con- rosine kinase (JAK-2) (22). Immediately after EPO binding, ditions, or non-humantissues. JAK-2 phosphorylates itself, the EPOR, and other proteins such The renin-angiotensin system regulates blood pressure, re- as STAT5, thus initiating a cascade of erythroid-specific sig- nal hemodynamics, and fluid and electrolyte homeostasis (41). naling (23, 24). This JAK2/STAT5 signaling plays a nonredun- The primary function of angiotensin during development is the dant, essential role in EPO/EPOR-mediated regulation of eryth- modulation of tissue growth and differentiation (42). The ropoiesis (24-27). growth effects of angiotensin II are dependent on the differen- The C-terminal cytoplasmic portion of EPORalso possesses tiation state of the cells at the time of exposure to angiotensin a negative growth-regulatory domain. Hematopoietic cell phos- II (43). Angiotensin II is a ligand for two distinct receptors, phatase (HCP, also known as SHP1) interacts with this portion type 1 and type 2. The angiotensin type 1 receptor (AT^, which of the EPORand down-modulates signal transduction (23-26). is found in liver, lung, adrenal gland, placenta, pituitary gland, Recruited by EPORY429, HCPattaches to the cytoplasmic aorta, heart, skeletal muscle, lymphocytes, monocytes and plate- EPORdomain and dephosphorylates JAK2.Inactivation of the lets, appears to have a major role in the modulation of cell HCPbinding site was shown to lead to prolonged phosphory- proliferation (44). The therapeutic effects of angiotensin-con- lation of JAK2/STAT5 (26, 27). Another negative regulator of verting enzyme (ACE) inhibitors and losartan, a specific an- erythropoiesis CIS-3 (also known as SOCS) also binds to the tagonist of ATj (45, 46), on post-transplant erythrocytosis or cytoplasmic portion of the EPO. CIS-3, binds to EPORY401 polycythemia in renal transplant patients indirectly link angio- and generates a erythroid specific inhibitory signal (28, 29). tensin II with the regulation of erythropoiesis. Wehave reported Thus, deletion of the C-terminal cytoplasmic portion of EPOR the presence of AT, on erythroid progenitors and found that its in a truncated EPORabolishes negative regulatory elements ligand, angiotensin II, augments EPOstimulation of erythro- and results in increased proliferation of erythroid progenitor poiesis (47). The involvement of JAK-2 kinase in angiotensin cells. II-mediated intracellular events suggests that the signal trans- Attempts to link a number of disorders characterized by duction pathways mediated by EPOand angiotensin II may dysregulation of erythropoiesis with mutations in EPOand overlap (48). EPORgenes have demonstrated that only a small proportion of cases of primary familial and congenital polycythemia Polycythemias Due to Defined (PFCP) are caused by EPORmutations (30, 31). EPORmuta- Molecular Lesions tions are only rarely found in erythroleukemia (32). Poly- cythemia vera (PV) and Diamond-Blackfan anemia are not Secondary Polycythemias: High A ffinity Hemoglobin Mutan ts, caused by mutations in EPO/EPOR(3 1). Methemoglobinemias, and 2, 3 Bisphosphoglyceromutase (Bpgm) Deficiency Insulin-like growth factor-l (IGF-I), angiotensin II and angio- Though first defined as a cause of congenital polycythemia, tensin II type I receptor and erythropoiesis high oxygenaffinity hemoglobinmutants are an uncommon Although in vitro studies of erythropoiesis have provided cause of congenital secondary polycythemia. More than 50 crucial information about the hierarchy of regulation of eryth- variants of both a and p globin genes have been described in ropoiesis, manyof these experiments were performed in the autosomal dominant polycythemia, and are characterized by presence of serum and serum-componentproteins capable of an increased oxygen affinity of hemoglobin (49). The hemo- stimulating as well as inhibiting erythropoietic activity (33- globin tetramer oscillates between the R (relaxed; fully oxy- 38). Using rigorous serum-free conditions, it has been shown genated hemoglobin) and T (tense; fully deoxygenated hemo- that IGF-1 can substitute for EPOfor normal erythroid pro- globin) states of the quaternary protein conformation requir- genitors and even more effectively for PVerythroid progeni- ing the cooperative interaction of globin subunits. Mutations tors (34, 39). Furthermore, it has also been observed that affecting the equilibrium between R and T states result in a anephric patients with no detectable EPOand normal
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