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NKL-Code in Normal and Aberrant Hematopoiesis

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NKL-Code in Normal and Aberrant Hematopoiesis cancers Review NKL-Code in Normal and Aberrant Hematopoiesis Stefan Nagel Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Inhoffenstr. 7B, 38124 Braunschweig, Germany; [email protected]; Tel.: +49-531-2616-167 Simple Summary: Gene codes represent expression patterns of closely related genes in particular tissues, organs or body parts. The NKL-code describes the activity of NKL homeobox genes in the hematopoietic system. NKL homeobox genes encode transcription factors controlling basic develop- mental processes. Therefore, aberrations of this code may contribute to deregulated hematopoiesis including leukemia and lymphoma. Normal and abnormal activities of NKL homeobox genes are described and mechanisms of (de)regulation, function, and diseases exemplified. Abstract: We have recently described physiological expression patterns of NKL homeobox genes in early hematopoiesis and in subsequent lymphopoiesis and myelopoiesis, including terminally differentiated blood cells. We thereby systematized differential expression patterns of eleven such genes which form the so-called NKL-code. Due to the developmental impact of NKL homeobox genes, these data suggest a key role for their activity in normal hematopoietic differentiation processes. On the other hand, the aberrant overexpression of NKL-code-members or the ectopical activation of non-code members have been frequently reported in lymphoid and myeloid leukemia/lymphoma, revealing the oncogenic potential of these genes in the hematopoietic compartment. Here, I provide an overview of the NKL-code in normal hematopoiesis and instance mechanisms of deregulation and oncogenic functions of selected NKL genes in hematologic cancers. As well as published clinical studies, our conclusions are based on experimental work using hematopoietic cell lines which represent useful models to characterize the role of NKL homeobox genes in specific tumor types. Citation: Nagel, S. NKL-Code in Normal and Aberrant Hematopoiesis. Keywords: NKL; homeobox; oncogene; T-ALL Cancers 2021, 13, 1961. https:// doi.org/10.3390/cancers13081961 Academic Editor: Daphne de Jong 1. Hematopoiesis The hematopoietic system comprises all cells derived from hematopoietic stem cells Received: 12 March 2021 (HSCs) (Figure1). Novel comprehensive sequencing approaches have extended the char- Accepted: 15 April 2021 Published: 19 April 2021 acterization and derivation of progenitors and mature blood cells [1–3]. Hematopoietic stem and progenitor cells generate common myeloid and lymphoid progenitors (CMPs and CLPs), founders of the myeloid and lymphoid lineages, respectively. CLPs produce Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in all types of lymphocytes comprising B-cells, T-cells, natural killer (NK)-cells and innate published maps and institutional affil- lymphoid cells (ILCs). Early B-cell development takes place in the bone marrow and begins iations. with the CLP-derived B-cell progenitor (BCP). BCPs differentiate into naïve B-cells via the pro-B- and pre-B-cell stages. Naïve B-cells migrate from the bone marrow into lymph nodes, spleen and other lymphoid tissues to undergo final differentiation into memory B-cells and plasma cells via the stage of germinal center (GC) B-cells. In contrast, CLP-derived early T-cell progenitors (ETPs) migrate into the thymus to complete their differentiation via the Copyright: © 2021 by the author. double negative (DN) and double positive (DP) stages into CD4 and CD8 single-positive Licensee MDPI, Basel, Switzerland. This article is an open access article T-cells. CMPs produce all types of myeloid cells including erythrocytes and granulocytes distributed under the terms and which comprise eosinophils, neutrophils and basophils. Intermediate differentiation steps conditions of the Creative Commons towards mature granulocytes include granulocyte macrophage progenitors (GMPs), early Attribution (CC BY) license (https:// and late pro-myelocytes, and meta-myelocytes. Further myeloid cells are megakaryocytes creativecommons.org/licenses/by/ and mast cells in addition to monocytes, which are able to differentiate into macrophages 4.0/). Cancers 2021, 13, 1961. https://doi.org/10.3390/cancers13081961 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x FOR PEER REVIEW 2 of 17 Cancers 2021, 13, 1961 2 of 17 are able to differentiate into macrophages or dendritic cells. Unlike lymphocytes, all or dendritic cells. Unlike lymphocytes, all types of myeloid cells develop within the types of myeloid cells develop within the bone marrow. bone marrow. Figure 1. Schematic presentation of hematopoiesis. This diagram depicts the progenitors and terminally differentiated cells ofFigure hematopoiesis, 1. Schematic comprising presentation the myeloidof hematopoie (left) andsis. lymphoidThis diagram (right depicts) lineage. the The progen followingitors and abbreviations terminally aredifferentiated used: BCP: B-cellcells of progenitor, hematopoiesis, CILCP: comprising commonILC the progenitor,myeloid (left CLP:) and common lymphoid lymphoid (right) progenitor,lineage. The CMP: following common abbreviations myeloid progenitor, are used: BCP: B-cell progenitor, CILCP: common ILC progenitor, CLP: common lymphoid progenitor, CMP: common myeloid ETP: early T-cell progenitor, HSC: hematopoietic stem cell, ILC(P): innate lymphoid cell (progenitor), LMP: lymphoid and progenitor, ETP: early T-cell progenitor, HSC: hematopoietic stem cell, ILC(P): innate lymphoid cell (progenitor), LMP: myeloid primed progenitor, NKP: NK-cell progenitor. Figure modified from www.pinterest.de. lymphoid and myeloid primed progenitor, NKP: NK-cell progenitor. Figure modified from www.pinterest.de. The main regulatory steps of hematopoiesis operate at the transcriptional level by The main regulatory steps of hematopoiesis operate at the transcriptional level by several transcription factors (TFs) identified as master genes for the development of several transcription factors (TFs) identified as master genes for the development of early early hematopoiesis, lymphopoiesis or myelopoiesis [3,4]. TAL1 and LYL1 are basic helix-turn-helixhematopoiesis, lymphopoiesis TF proteins and or regulate myelopoies vitalis steps [3,4]. in earlyTAL1 and and late LYL1 hematopoiesis are basic he- [5]. GATAlix-turn-helix factors areTF proteins zinc-finger and proteins regulate that vital control steps hematopoietic in early andstem late cellshematopoiesis (GATA2), ery-[5]. thropoiesisGATA factors (GATA1), are zinc-finger and NK- proteins and T-cell that development control hematopoietic (GATA3) [6stem,7]. Additionalcells (GATA2), TFs controllingerythropoiesis specific (GATA1), processes and NK- in hematopoietic and T-cell development differentiation (GATA3) are EBF1[6,7]. Additional and PAX5 (de-TFs velopmentcontrolling ofspecificB-cells processes), BCL11B in (T-cells), hematopoietic NFIL3 differentiation (NK-cells), ID2 are (ILCs), EBF1 andand SPI1/PU.1PAX5 (de- (myeloidvelopment cells) of B-cells), [8–12]. TheseBCL11B developmental (T-cells), NFIL3 regulators (NK-cells), belong ID2 to (ILCs), different and protein SPI1/PU.1 fam- ilies,(myeloid demonstrating cells) [8–12]. that These various developmental types of TFsregulators mediate belong the transcriptional to different protein control fami- of hematopoiesis.lies, demonstrating that various types of TFs mediate the transcriptional control of hem- atopoiesis. 2. Classification of Homeobox Genes 2. ClassificationHomeobox genesof Homeobox encode one Genes of the largest groups of TFs in the human genome [13]. Generally,Homeobox they regulate genes encode basic development one of the largest and differentiationgroups of TFs in boththe human embryogenesis genome [13]. and theGenerally, adult. Thesethey regulate genes share basic the development conserved homeobox and differentiation which is 180 in bpboth long embryogenesis and encodes theand homeodomainthe adult. These at genes the protein share the level. conser Thisved domain homeobox consists which of 60 is amino180 bp acidlong residues and en- whichcodes the form homeodomain three helices, at generating the protein a specific level. This 3D structure. domain consists The homeodomain of 60 amino performsacid res- specificidues which interactions form three with helices, DNA, chromatin, generating non-coding a specific 3D RNAs, structure. and cooperating The homeodomain TFs, thus representingperforms specific the coreinteractions of their with gene DNA, regulatory chromatin, activities non-coding [14]. Specific RNAs, DNA and contactscooperating are realizedTFs, thus by representing helix 3 which the fits core into theof majortheir ge groovene regulatory [15]. The remainingactivities [14]. helices Specific stabilize DNA the domaincontacts structureare realized and, by together helix 3 withwhich flanking fits into amino the major acid groove residues, [15]. allow The additional remaining DNA hel- interactions (Figure2). Cancers 2021, 13, x FOR PEER REVIEW 3 of 17 ices stabilize the domain structure and, together with flanking amino acid residues, allow additional DNA interactions (Figure 2). Cancers 2021, 13, 1961 3 of 17 Figure 2. Schematic structure of NKL homeodomain proteins. N: N-terminal end; C: C-terminal end; EH1: conserved engrailed homology domain consisting of about 8 amino acid residues (shown in green); the conserved homeodomain consists of 60 amino acid residues which generate three helices (H1-3) and is shown in blue; the N- and C-terminal parts
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