A role for RUNX1 in hematopoiesis and myeloid leukemia | SpringerLink

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Since its discovery from a translocation in leukemias, the runt-related transcription factor 1/acute myelogenous leukemia-1 (RUNX1/AML1), which is widely ...

Int J Hematol (2013) 97:726–734 DOI 10.1007/s12185-013-1347-3

REVIEW ARTICLE

A role for RUNX1 in hematopoiesis and myeloid leukemia Motoshi Ichikawa • Akihide Yoshimi • Masahiro Nakagawa • Nahoko Nishimoto • Naoko Watanabe-Okochi • Mineo Kurokawa

Received: 12 October 2012 / Revised: 15 April 2013 / Accepted: 16 April 2013 / Published online: 24 April 2013 Ó The Japanese Society of Hematology 2013

Abstract Since its discovery from a translocation in leukemias, the runt-related transcription factor 1/acute myelogenous leukemia-1 (RUNX1/AML1), which is widely expressed in hematopoietic cells, has been extensively studied. Many lines of evidence have shown that RUNX1 plays a critical role in regulating the development and precise maintenance of mammalian hematopoiesis. Studies using knockout mice have shown the importance of RUNX1 in a wide variety of hematopoietic cells, including hematopoietic stem cells and megakaryocytes. Recently, target molecular processes of RUNX1 in normal and malignant hematopoiesis have been revealed. Although RUNX1 is not required for the maintenance of hematopoietic stem cells, it is required for the homeostasis of hematopoietic stem and progenitor cells, and expansion of hematopoietic stem and progenitor cells due to RUNX1 deletion may be an important cause of human leukemias. Molecular abnormalities cooperating with loss of RUNX1 have also been identified. These findings may lead to a further understanding of human leukemias, and suggest novel molecular targeted therapies in the near future. Keywords RUNX1  Hematopoiesis  Leukemia  Hematopoietic stem cells  Megakaryocytes

M. Ichikawa  A. Yoshimi  M. Nakagawa  N. Nishimoto  N. Watanabe-Okochi  M. Kurokawa (&) Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan e-mail: [email protected]

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Introduction Leukemia is believed to develop through multiple molecular processes, such that cause uncontrolled proliferation of hematopoietic cells and block in the differentiation or maturation of hematopoietic progenitors. Since the discovery of the Philadelphia chromosome in chronic myelogenous leukemia cells in 1960, such molecular processes are vigorously investigated through the analysis of distinct chromosomal abnormalities often found in leukemias. Runt-related transcription factor 1 (RUNX1), also known as acute myelogenous leukemia-1 (AML1), was initially found from the translocational breakpoint of chromosome 21 in the t(8;21)(q22;q22) chromosomal translocation most frequently found in acute myelogenous leukemia (AML). Since RUNX1 is discovered as a transcription factor that binds to viral enhancers, it is also called as PEBP2aB (polyoma enhancer binding protein 2 alpha B) and CBFA2 (core binding factor alpha 2). RUNX proteins are evolutionally conserved, and there are two runt homologs in Drosophila, namely runt and lozenge. In mammals, there are three RUNX proteins, i.e., RUNX1, RUNX2, and RUNX3. RUNX proteins have a DNAbinding domain in its N-terminal portion, which consists of 128-amino-acid domain evolutionally conserved from Drosophila to humans. There is also conserved C-terminal 5-amino-acid motif, VWRPY, in all RUNX proteins (Fig. 1). In the hematopoietic cells, RUNX1 is constitutively expressed in all lineages except for mature erythroid cells [1], and has been shown to be critical for hematopoietic development. RUNX1 is involved in a number of chromosomal translocations found in leukemias, and is also mutated in various kinds of leukemia. Most of these mutations result in loss or impairment of RUNX1 function.

RUNX1 in normal and malignant hematopoiesis

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Fig. 1 An illustration of the RUNX proteins, its mutants and the cofactor CBFb. RUNX proteins have an evolutionally conserved runt domain near the N-terminus, and a VWRPY motif near their C-terminus. The runt domain is also conserved in the leukemic

chimera proteins RUNX1-ETO, RUNX1-EVI1, and TEL-RUNX1. The cofactor CBFb and its leukemic mutant CBFb-SMMHC are also shown

Thus, RUNX1 acts as a critical regulator of hematopoiesis and its altered function results in leukemogenesis. In this article, we will discuss the recently revealed critical function of RUNX1 in normal hematopoiesis and the participation of altered RUNX1 function in leukemias.

However, once adult-type hematopoiesis develops in the embryos, continuous expression of RUNX1 is not required for the maintenance of HSCs in the adult mice. Studies using conditional knockout mice show that excision of the Runx1 loci does not cause hematopoietic failure in adult mice [8–10] (Fig. 2). It has also been shown that once HSCs emerge from the vascular endothelial cells in the embryos, Runx1 is not required for the maintenance of Vav1-expressing HSCs [6]. On the other hand, several lines of evidence show that Runx1 represses the number of HSCs in the adult stage (Fig. 2). For example, forced expression of the full-length RUNX1 causes loss of HSC function of the bone marrow cells, while truncated isoform of RUNX1 promotes engraftment of HSCs when transplanted to irradiated mice [11]. Bone marrow stem cell fractions, i.e., Lineage-negative, c-Kit positive, Sca-1positive and CD34-negative fraction (CD34- LSK) or Hoechst 33342-side population cells are expanded in the Runx1-conditional knockout mice [9, 12, 13]. We have shown that the number of HSCs with long-term repopulating capacity is increased in the Runx1-deleted bone marrow [12]. In contrast, the expanding HSCs induce stem cell exhaustion in a long term due to a decreased expression of niche factor CXCR4 [14]. Recently, Cai et al. used a mice with hematopoietic cell-specific deletion of Runx1 and showed that the effect of Runx1 deletion on the longterm HSC frequency was minimal, and that changes in the phenotypical HSC frequency are limited [15]. In spite of the partially conflicting results, all these reports invariably

RUNX1 is a critical regulator of normal hematopoiesis RUNX1 was discovered as a transcription factor which binds to viral enhancers, and binds to the consensus DNA sequence TGTGGT or TGCGGT [2]. Through binding to its consensus sequence, RUNX1 regulates the expression of the hematopoiesis-specific genes, including cytokine receptors such as M-CSFR, cytokines such as IL-3 and GM-CSF, T and B cell receptors, and megakaryocytespecific genes such as PF4. Runx1 deficient mice die in their embryonic stage around day 12.5 postcoitus because of a lack of definitive hematopoiesis in the vascular endothelial cells, and subsequent hemorrhage in the central nervous system probably due to defective angiogenesis [3– 5]. It has also been shown that in the embryos, hematopoietic stem cells (HSCs) emerge from Runx1-expressing, vascular-endothelial-cadherin-positive endothelial cells, and Runx1 activity is essential for HSC formation from these ‘hemogenic endothelium’ [6, 7]. Through these observations, RUNX1 has been recognized as a mandatory transcription factor in the development of embryonic hematopoiesis.

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Fig. 2 Regulation of HSCs and differentiated hematopoietic cells by RUNX1 (modified from [80]). RUNX1 is required for the formation of HSCs in the embryos. It is also essential for the maturation of T and B lymphocytes and megakaryocytes at the polyploidization stage; however, proliferation of HSCs and the myeloid progenitors are

negatively regulated by RUNX1. AGM aorto-gonado-mesonephros region, CLP common lymphocyte progenitor, CMP common myeloid progenitor, GMP granulocyte–macrophage progenitor, MEP megakaryocyte–erythrocyte progenitor

showed that the phenotypical hematopoietic stem/progenitor cell fraction is expanded when Runx1 is deleted.

development of demarcation membranes in the megakaryocytes [8] (Fig. 2). Interestingly, RUNX1 mutations have been found in pedigrees of a rare inherited human disease familial platelet disorder with propensity to develop AML (FPD/AML). First described in 1985, FPD/AML has been known to be a rare inherited hematopoietic failure syndrome in which affected patients develop bleeding tendency, modest thrombocytopenia with normal-sized platelets, and functional platelet defect in some cases, and are susceptible to leukemia development most frequently in their 30s or 40s [16]. Since mutations in the RUNX1 locus in affected individuals were found in 1999, at least 27 pedigrees have been reported to date [17–30]. The low megakaryocyte ploidy level and defective platelet formation were reproduced by the in vitro megakaryopoiesis of human FPD/AML pedigrees [31]. Although RUNX1 is required for the maturation of megakaryocytes, its critical transcriptional target in megakaryopoiesis was difficult to identify as the rarity of megakaryocytes in the bone marrow. Recently, p19INK4D, NR4A3, ALOX12, and myosin heavy chain genes have been identified as possible targets of RUNX1 in

Requirement of RUNX1 for megakaryocytes and platelets Importantly, RUNX1 is essential for the maturation of megakaryocytes and the production of platelets in adult hematopoiesis. Runx1 conditional knockout mice show marked but nonlethal thrombocytopenia soon after hematopoietic cell-specific ablation of Runx1 [8, 9]. Megakaryocytes undergo a specific cell cycle process called endomitosis, in which the nuclei of the megakaryocytes are polyploidized without being subdivided into daughter nuclei. Through endomitosis, the nuclei of megakaryocytes acquire high DNA amount, which is up to 32 N or 64 N, and this process is thought to be important in the megakaryocyte maturation and platelet production. In the Runx1deleted thrombocytopenic mice, megakaryocytes in the bone marrow are small in size, the polyploidization processes of which are defective, and showed defective

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RUNX1 in normal and malignant hematopoiesis

megakaryocytes, and their roles in megakaryocyte polyploidization are elucidated [31–36]. RUNX1 binds to and downregulate the p19INK4D promoter resulting in promotion of megakaryocyte polyploidization, and RUNX1 regulates endomitosis by regulating non-muscle myosin chain genes MYL9 and MYH10 [31–33]. Expression profiling of platelets revealed decreased expression of 12-lipoxygenase encoded by the ALOX12 gene, which catalyzes 12-hydroxyeicosatetraenoic acid production from arachidonic acid [35]. Analyses on promoter activation of ALOX12 by RUNX1 revealed that ALOX12 is a direct target of RUNX1 in platelets; however, its function in platelet production remains to be elucidated.

A role for abnormal RUNX1 in leukemogenesis RUNX1 mutations in leukemias were initially reported as chimeric genes formed by chromosomal translocations including t(8;21), t(3;21), and t(16;21). Afterwards, RUNX1 mutations were also found in the myeloid malignancies with normal karyotype, including FAB classification M0 AMLs and myelodysplastic syndromes (MDS) [37, 38]. In the FAB M0 AMLs, RUNX1 mutations were detected in more than 40 % of cases [39], and RUNX1 point mutations are also detected in patients with myeloproliferative neoplasms (MPNs) transformed into AMLs [40]. Thus, RUNX1 is one of the most frequently mutated genes in human AMLs. Initially found in human leukemias, the chimeric gene product of t(8;21), RUNX1-RUNX1T1 (also known as RUNX1-ETO or AML1-MTG8) has been shown to repress the function of normal RUNX1 in hematopoiesis [41]. Interestingly, chimeric genes t(3;21) and t(16;21) produce AML1-EVI1 and AML1-MTG16, respectively, that also repress RUNX1 function (Fig. 1). All these mutants bear the runt domain of RUNX1 and lack the C-terminal domains, suggesting that loss of RUNX1 function is a common feature of leukemogenesis by these mutants. The chimeric protein RUNX1-ETO consists of the runt domain of RUNX1 and almost the entire coding region of ETO. Within the ETO-derived region of RUNX1-ETO, 4 functional domains, namely Nervy homology region (NHR)1, NHR2, NHR3, and NHR4 have been identified. Through inhibition of the normal RUNX1 function, RUNX1-ETO represses the expression of myeloid-specific genes, and thus has been believed to cause maturation block of the myeloid cells [42, 43]. According to multiple-hit mutation models, genetic mutations causing leukemia are believed to be subdivided into two classes of mutations; class I mutations that are believed to cause uncontrolled proliferation or block in apoptosis of the cells, and class II mutations that cause

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block in development of maturation of the cells [44]. Class I mutations include those causing abnormal tyrosine kinase activity such as BCR-ABL in chronic myelogenous leukemia and constitutive expression of antiapoptotic signaling molecules such as bcl-2 and Myc in B cell lymphomas. Since loss of RUNX1 function has been supposed to cause block in the differentiation of hematopoietic cells, RUNX1 mutations have been recognized as class II mutations. However, it has been demonstrated that the myeloid cell differentiation of the Runx1-deleted mice are almost normal [8]. On the other hand, HSC population is expanded in the bone marrow cells with defective RUNX1 function, suggesting that loss of RUNX1 function also acts as a class I mutation. Jacob et al. [14] show that HSCs that bear capability of reconstituting long-term hematopoiesis are expanded in the RUNX1-deleted bone marrow, but these RUNX1-deleted stem cells readily exhaust. They suggest that rescue from such exhaustion may act as a second-hit mutation in RUNX1-deletion-related leukemias. Collectively, RUNX1 mutations may function as both class I and class II mutations at once. However, exhaustion of the HSCs has not been reproduced in another study [15], and the details of HSC expansion due to RUNX1 loss and the function of secondary mutation remains to be elucidated. In the mouse models, Runx1-deleted mice do not develop leukemia [8]. Leukemic RUNX1-ETO was introduced to the hematopoietic cells using retroviral vectors, conditional knock-in systems, and transgenic strategies [45–48]. Importantly, mice expressing RUNX1-ETO in their bone marrow cells do not develop leukemia. Although the HSC population is expanded in the bone marrow, leukemia occurs in these mice only after treatment with alkylating agents for additional secondary genetic mutations. More recently, Yan et al. [49] reported that deletion of the C-terminal NCoR/SMRT-interacting domain of RUNX1-ETO results in the formation of more potent leukemogenic protein. They later discovered that use of an alternative exon of ETO, exon 9a, results in a formation of alternatively spliced AML1-ETO9a that has a very similar structure to their C-terminal truncated leukemogenic protein [50]. Interestingly, AML1-ETO9a is expressed in human leukemic cells. Introduction of AML1-ETO9a into mouse hematopoietic cells results in the rapid development of leukemia in the transplanted mice, suggesting that AML1-ETO9a does not require additional mutations [50]. The splicing variant form of leukemic protein that possesses potent leukemogenic activity suggests a previously unknown mechanism of tumorigenesis. Since loss of RUNX1 itself is not sufficient for causing leukemias, ‘‘second-hit’’ genetic mutations have been extensively sought. To determine the molecule which synergistically acts with RUNX1 loss in hematopoiesis, Motoda et al. used the BXH2 mouse strain which bears an

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Fig. 3 Inhibition of normal RUNX1 function by RUNX1 point mutations and RUNX1-ETO. While both of these mutants repress normal RUNX1 function, ‘‘second hit’’ mutations and subsequent AML types are different between these mutations

ecotropic murine leukemia retrovirus that functions as an insertional mutagen to spontaneously induce myeloid leukemias within 1 year in more than 90 % of the animals, and the retroviral insertional sites can be identified using inverse PCR. They showed that BXH2 myeloid leukemias develop in a shorter period in Runx1-haploinsufficient mice than in the controls, and identified several common retroviral integration sites in these leukemic mice [51]. Among these, the Ras gene family and its upstream factor genes including the receptor tyrosine kinases Kit and Flt3 are frequently mutated in the RUNX1-related leukemias. Using the conditional Runx1 knockout mice, they showed that activated Ras mutation and loss of Runx1 act synergistically to develop myeloid leukemias, and suggested that RUNX1 deficiency rescues the cellular senescence and apoptosis induced by oncogenic N-RAS [51]. Watanabe-Okochi et al. used a different approach in searching the synergistic mechanism with loss of RUNX1 function in hematopoiesis. They transduced RUNX1 mutants derived from patients with MDS into the mouse bone marrow progenitor cells using retrovirus, and found that mice transplanted with bone marrow cells expressing the MDS-derived RUNX1 mutants die with MDS-like hematological abnormalities [52]. They also report that a point mutation in the runt domain of RUNX1 (AML1 D171N) cooperates with EVI1, a transcription factor required for the maintenance of normal and leukemic stem cells [53]. Interestingly, the chimeric protein RUNX1EVI1, which results from the chromosomal translocation t(3;21) in AMLs and chronic myelogenous leukemia, acts as a dominant-negative form for normal RUNX1 function and share many molecular properties with EVI1 [54, 55]. Therefore, certain RUNX1 mutants employ EVI1 as a second-hit molecule in developing AML. In human leukemias, genetic alterations coexisting with RUNX1 mutants are recently reported. Among these, the partial tandem duplication in the mixed lineage leukemia

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gene (MLL-PTD) is frequently found with the AML cases with point mutation in the RUNX1 gene [56, 57]. MLL is located in the long arm of the chromosome 11 (11q23) and is frequently translocated with various genes in leukemias. The physical and functional interaction between RUNX1 and MLL in the leukemogenesis has been recently reported. Huang et al. [58] have shown that this interaction is essential for RUNX1-mediated transcriptional upregulation of PU.1 through histone modification and that N-terminus mutations of RUNX1 lose their capacity to bind to MLL and to activate PU.1. Although both of the RUNX1 point mutation and the translocation t(8;21) results in the loss of RUNX1 function and expansion of hematopoietic stem/progenitor cells, leukemogenic mechanisms underlying the two genetic alterations are, presumably, quite different. The clinical features of the leukemias caused by these mutations apparently differ from each other, i.e., the MDS or AML M0 with RUNX1 point mutations which show poor prognoses and AML with maturation (FAB M2) caused by the t(8;21) which show favorable prognosis [59]. Poor prognosis of the relapsed t(8;21) leukemias imply that secondary genetic hits in the RUNX1-related leukemias may be the cause of such poor prognoses, although the molecular mechanisms should be further evaluated (Fig. 3).

Molecules which cooperatively act with RUNX1 RUNX1 forms a heterodimer complex with its cofactor, CBFb. Mutant mice deficient in CBFb die in utero with very similar phenotype with RUNX1, such as developmental defect in definitive hematopoiesis around embryonic day 12.5 [60]. Mutation of CBFb is also frequent in AML. In FAB M4Eo AML, inversion of the chromosome 16 forming a chimeric protein CBFB-MYH11 is frequently found. Through the runt domain, RUNX1 binds to CBFb

RUNX1 in normal and malignant hematopoiesis

and forms a heterodimeric complex. CBFb binding to RUNX1 enhances DNA binding affinity of the runt domain [61], and protects RUNX1 from ubiquitination and proteasomal degradation [62]. Since RUNX1-ETO binds to CBFb more efficiently than wild-type RUNX1, it has been speculated that the dominant-negative effect of the chimeric protein may be due to the increased affinity to its cofactor molecule [63]. However, it was not clear whether the binding to CBFb was essential for the leukemogenesis of RUNX1-ETO. A mutation in the Runt domain, called R174Q, found from the FPD/AML case disrupts only the DNA binding but not CBFb binding of RUNX1 [64]. Replacement for this mutation at the Runt domain of the AML1-ETO9a chimeric protein abolishes the leukemogenic capacity of AML1-ETO9a, suggesting that DNA binding of AML1ETO9a is essential for the development of leukemia [65]. However, requirement of CBFb binding of RUNX1-ETO in leukemogenesis remains controversial, because RUNX1ETO mutants with defective heterodimerization with CBFb and intact DNA binding (Y113A/T161A and M106V/ A107T) show inconsistent leukemogenic activity [66–68]. A number of molecules interact with RUNX1 and modulate its transcriptional activity. For example, RUNX1 is phosphorylated by kinases including ERK, HIPK2, and cyclin-dependent kinases [69–72]. There are five phosphorylated serine or threonine residues in RUNX1, the importance of which are lineage-dependent. While RUNX1 mutant carrying four phosphorylation-deficient mutations of the five residues result in impaired T cell differentiation, mutations in all the five residues are required for the loss of early hematopoietic activity of RUNX1 [73]. RUNX1 is also methylated by PRMT1 resulting in an abrogated SIN3A binding and a potentiated transcriptional activity [74]. Recently, we reported a novel mechanism of RUNX1 function in which RUNX1 acts as a cytoplasmic regulator of NF-jB signaling, rather than a transcription factor regulating gene expression in the nucleus [75]. RUNX1 interacts with IjB kinase complex in the cytoplasm, resulting in an repressed NF-jB signaling, through attenuated degradation of IjB through the ubiquitin–proteasome pathway [75]. Interestingly, this attenuation of NF-jB signaling does not occur when mutant RUNX1 is overexpressed. Moreover, proliferation of leukemia cells expressing mutant RUNX1 is blocked by the NF-jB inhibitor BMS-345541 or the proteasome inhibitor bortezomib, suggesting targeting this pathway should be promising in the regulation of RUNX1-related leukemias [75]. Target genes of RUNX1 include various classes of genes, such as transcription factors [76], cytokines, cytokine receptors, and microRNAs [77, 78]. Among these,

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regulation of cell cycle and apoptosis-related genes, which may cause enhanced proliferation of the cells with aberrant RUNX1 function, is of interest in leukemia cells. We have shown that the loss of Runx1 in the MLL–ENL leukemia cells results in an acceleration of leukemia in individual animals, and RUNX1 deletion causes down-regulation of p19ARF and enhanced proliferation of the MLL–ENL leukemia cells [79]. This observation may explain at least partially the cell-proliferating capacity of RUNX1 deletion in leukemias.

Summary Undoubtedly, RUNX1 plays a central role in normal and malignant hematopoiesis. Although its participation in mammalian hematopoiesis has been extensively studied, the molecular mechanisms underlying the emergence of HSCs in the embryos, precise differentiation of hematopoietic progenitor cells, and malignant transformation, remains to be elucidated. Recently, however, knowledge in the target genes and elucidation of its function in normal and malignant hematopoiesis are continuously expanding. These studies should lead to the way to find the candidates for molecular therapeutic targets. Conflict of interest of interest.

The authors declare that they have no conflict

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