Evi-1 promotes para-aortic splanchnopleural hematopoiesis through up-regulation of GATA-2 and repression of TGF-b signaling

Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Cancer Science (Impact Factor: 3.52). 08/2008; 99(7):1407-13. DOI: 10.1111/j.1349-7006.2008.00842.x
Source: PubMed


Evi-1 is a zinc-finger transcriptional factor whose inappropriate expression leads to leukemic transformation in mice and humans. Recently, it has been shown that Evi-1 regulates proliferation of hematopoietic stem/progenitor cells at embryonic stage via GATA-2 up-regulation; however, detailed mechanisms underlying Evi-1-mediated early hematopoiesis are not fully understood. We therefore evaluated hematopoietic potential of Evi-1 mutants using a cultivation system of murine para-aortic splanchnopleural (P-Sp) regions, and found that both the first zinc finger domain and the acidic domain were required for Evi-1-mediated hematopoiesis. The hematopoietic potential of Evi-1 mutants was likely to be related to its ability to up-regulate GATA-2 expression. We also showed that the decreased colony forming capacity of Evi-1-deficient P-Sp cells was successfully recovered by inhibition of TGF-b signaling, using ALK5 inhibitor or retroviral transfer of dominant-negative-type Smad3. Our findings suggest that Evi-1 promotes hematopoietic stem/progenitor expansion at the embryonic stage through up-regulation of GATA-2 and repression of TGF-beta signaling.

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Available from: Tomohiko Sato, Dec 15, 2014
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    • "Indeed, EVI1 harbors several hallmark functions that are normally associated with leukemogenesis, with the following four possibly being the most intriguing. First, EVI1 regulates the transcription of the transcription factor genes GATA2 and PBX1, both of which play critical roles in the maintenance of hematopoietic stem cells, as well as the tumor suppressor gene PTEN (Sato et al., 2008; Shimabe et al., 2009; Yoshimi et al., 2011; Yuasa et al., 2005). Second, EVI1 binds to the transcription factors RUNX1, PU.1, and GATA1, thereby inhibiting their activity and blocking the differentiation of hematopoietic progenitors (Laricchia-Robbio et al., 2006, 2009; Senyuk et al., 2007). "
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    ABSTRACT: Chromosomal inversion between 3q21 and 3q26 results in high-risk acute myeloid leukemia (AML). In this study, we identified a mechanism whereby a GATA2 distal hematopoietic enhancer (G2DHE or -77-kb enhancer) is brought into close proximity to the EVI1 gene in inv(3)(q21;q26) inversions, leading to leukemogenesis. We examined the contribution of G2DHE to leukemogenesis by creating a bacterial artificial chromosome (BAC) transgenic model that recapitulates the inv(3)(q21;q26) allele. Transgenic mice harboring a linked BAC developed leukemia accompanied by EVI1 overexpression-neoplasia that was not detected in mice bearing the same transgene but that was missing the GATA2 enhancer. These results establish the mechanistic basis underlying the pathogenesis of a severe form of leukemia through aberrant expression of the EVI1 proto-oncogene.
    Cancer cell 04/2014; 25(4). DOI:10.1016/j.ccr.2014.02.008 · 23.52 Impact Factor
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    • "PRDM16 is similar in structure to PRDM3, which has been previously demonstrated to bind and thereby inactivate SMAD3 proteins through its DNA binding domain-1 (Zn-finger domain-1) and repress TGF-β cell growth-inhibitory signaling [102]. PRDM3 and PRDM16, however, bind SMADs and recruit CtBP, which in turn join histone deacetylases (HDACs) to deacetylate histones and repress SMAD mediated transcription [10,21,102,103,104,105]. "
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    ABSTRACT: PRDM (PRDI-BF1 and RIZ homology domain containing) protein family members are characterized by the presence of a PR domain and a variable number of Zn-finger repeats. Experimental evidence has shown that the PRDM proteins play an important role in gene expression regulation, modifying the chromatin structure either directly, through the intrinsic methyltransferase activity, or indirectly through the recruitment of chromatin remodeling complexes. PRDM proteins have a dual action: they mediate the effect induced by different cell signals like steroid hormones and control the expression of growth factors. PRDM proteins therefore have a pivotal role in the transduction of signals that control cell proliferation and differentiation and consequently neoplastic transformation. In this review, we describe pathways in which PRDM proteins are involved and the molecular mechanism of their transcriptional regulation.
    Biology 03/2013; 2(1):107-41. DOI:10.3390/biology2010107
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    • "Literature searches revealed that all 8 transcription factors have been implicated in hematopoiesis. In particular, Evi1 is an oncogenic transcription factor in myeloid leukemias, and may regulate normal hematopoiesis by interacting with transcription factors in the Gata family [60], [61]. Deletion of the ubiquitously expressed basic leucine zipper transcription factor AFT4 leads to severe anemia [62]. "
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    ABSTRACT: Hematopoietic stem cells (HSC) are rare, multipotent cells capable of generating all specialized cells of the blood system. Appropriate regulation of HSC quiescence is thought to be crucial to maintain their lifelong function; however, the molecular pathways controlling stem cell quiescence remain poorly characterized. Likewise, the molecular events driving leukemogenesis remain elusive. In this study, we compare the gene expression profiles of steady-state bone marrow HSC to non-self-renewing multipotent progenitors; to HSC treated with mobilizing drugs that expand the HSC pool and induce egress from the marrow; and to leukemic HSC in a mouse model of chronic myelogenous leukemia. By intersecting the resulting lists of differentially regulated genes we identify a subset of molecules that are downregulated in all three circumstances, and thus may be particularly important for the maintenance and function of normal, quiescent HSC. These results identify potential key regulators of HSC and give insights into the clinically important processes of HSC mobilization for transplantation and leukemic development from cancer stem cells.
    PLoS ONE 01/2010; 5(1):e8785. DOI:10.1371/journal.pone.0008785 · 3.23 Impact Factor
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