Stem cell exhaustion due to Runx1 deficiency is prevented by Evi5 activation in leukemogenesis

Jacob, Bindya; Osato, Motomi; Yamashita, Naoto; Wang, Chelsia Qiuxia; Taniuchi, Ichiro; Littman, Dan R.; Asou, Norio; Ito, Yoshiaki

doi:10.1182/blood-2009-07-232249

Cited by 94 publications

(97 citation statements)

References 43 publications

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“…This observation could have been due to a defect in homing of Runx1 ⌬/⌬ cells, as described previously, 38 to the lack of survival in the BM niche, or to an exhaustion of the transplanted stem cell pool described previously for Runx1 ⌬/⌬ cells. 38,39 Interestingly, a recent study identified CXCR4 and CD49b, factors that are crucial for the interaction of HSCs with the BM niche, as Runx1 target genes, providing a possible explanation for the low engraftment potential of Runx1 ⌬/⌬ HSPCs. 38 Therefore, the multiple roles of Runx1 in HSPCs seem to complicate in vivo studies using engraftment experiments.…”

Section: Discussionmentioning

confidence: 99%

Polycomb group ring finger 1 cooperates with Runx1 in regulating differentiation and self-renewal of hematopoietic cells

Roß

Sedello

Todd

et al. 2012

Blood

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AbstractThe transcription factor runt-related transcription factor 1 (Runx1) is essential for the establishment of definitive hematopoiesis during embryonic development. In adult blood homeostasis, Runx1 plays a pivotal role in the maturation of lymphocytes and megakaryocytes. Furthermore, Runx1 is required for the regulation of hematopoietic stem and progenitor cells. However, how Runx1 orchestrates self-renewal and lineage choices in combination with other factors is not well understood. In the present study, we describe a genome-scale RNA interference screen to detect genes that cooperate with Runx1 in regulating hematopoietic stem and progenitor cells. We identify the polycomb group protein Pcgf1 as an epigenetic regulator involved in hematopoietic cell differentiation and show that simultaneous depletion of Runx1 and Pcgf1 allows sustained self-renewal while blocking differentiation of lineage marker–negative cells in vitro. We found an up-regulation of HoxA cluster genes on Pcgf1 knock-down that possibly accounts for the increase in self-renewal. Moreover, our data suggest that cells lacking both Runx1 and Pcgf1 are blocked at an early progenitor stage, indicating that a concerted action of the transcription factor Runx1, together with the epigenetic repressor Pcgf1, is necessary for terminal differentiation. The results of the present study uncover a link between transcriptional and epigenetic regulation that is required for hematopoietic differentiation.

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Section: Discussionmentioning

confidence: 99%

Polycomb group ring finger 1 cooperates with Runx1 in regulating differentiation and self-renewal of hematopoietic cells

Roß

Sedello

Todd

et al. 2012

Blood

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“…Runx1 is one of the most frequently mutated genes in acute myeloid leukemia, representing the first hit that expands blood progenitors, creating a reservoir for further genetic alterations to occur (15). The knowledge that Runx1 facilitates its own degradation by promoting the Runx1-Smad6-Smurf1-proteasome axis could be harnessed as a therapeutic strategy if Runx1 fusion proteins can be shuttled to the proteasome by Smad6 as efficiently as wild-type Runx1.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, haploinsufficiency results in the early emergence of HSCs from the aorta-gonadmesonephros (AGM) (5,22). Interestingly, the deletion of Runx1 in adult HSCs per se leads to the initial expansion and subsequent exhaustion of HSCs (15). The partial or complete loss of RUNX1 function is a common underlying first hit in leukemia, although it is not sufficient per se to cause full-blown leukemia (35).…”

mentioning

confidence: 99%

A Runx1-Smad6 Rheostat Controls Runx1 Activity during Embryonic Hematopoiesis

Knezevic

Bee

Wilson

et al. 2011

Molecular and Cellular Biology

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The oncogenic transcription factor Runx1 is required for the specification of definitive hematopoietic stem cells (HSC) in the developing embryo. The activity of this master regulator is tightly controlled during development. The transcription factors that upregulate the expression of Runx1 also upregulate the expression of Smad6, the inhibitory Smad, which controls Runx1 activity by targeting it to the proteasome. Here we show that Runx1, in conjunction with Fli1, Gata2, and Scl, directly regulates the expression of Smad6 in the aorta-gonad-mesonephros (AGM) region in the developing embryo, where HSCs originate. Runx1 regulates Smad6 activity via a novel upstream enhancer, and Runx1 null embryos show reduced Smad6 transcripts in the yolk-sac and c-Kit-positive fetal liver cells. By directly regulating the expression of Smad6, Runx1 sets up a functional rheostat to control its own activity. The perturbation of this rheostat, using a proteasomal inhibitor, results in an increase in Runx1 and Smad6 levels that can be directly attributed to increased Runx1 binding to tissue-specific regulatory elements of these genes. Taken together, we describe a scenario in which a key hematopoietic transcription factor controls its own expression levels by transcriptionally controlling its controller.Cell fate decisions in the developing embryo are coordinated by complex gene regulatory networks. These networks are composed primarily of transcription factors (TFs) and cis-regulatory modules, which together control the rates of gene expression. As a consequence, transcriptional regulatory networks control cell function and identity by controlling the types and amounts of protein that are produced in a cell (7). Largely through the systematic analysis of transcription networks in bacteria and yeast, it is now known that information flow through complex networks is controlled by deploying a recur-

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“…RUNX1 is abrogated by multiple types of genetic alterations in human hematological malignancies [3][4][5] and is critical for the generation and maintenance of hematopoietic stem cells (HSCs). [6][7][8][9][10] Runx1 regulates the expression of stemnessand niche-related factors, such as Bmi1, Cxcr4, and integrin a 2 , deregulation of which in adult Runx1 knockout (KO) mice led to an expanded hematopoietic stem/progenitor cell (HSPC) compartment and subsequent stem cell exhaustion. [6][7][8][9][10][11][12] In addition, adult Runx1 KO mice show abnormal megakaryocytic differentiation and defective lymphoid development.…”

Section: Introductionmentioning

confidence: 99%

“…[6][7][8][9][10] Runx1 regulates the expression of stemnessand niche-related factors, such as Bmi1, Cxcr4, and integrin a 2 , deregulation of which in adult Runx1 knockout (KO) mice led to an expanded hematopoietic stem/progenitor cell (HSPC) compartment and subsequent stem cell exhaustion. [6][7][8][9][10][11][12] In addition, adult Runx1 KO mice show abnormal megakaryocytic differentiation and defective lymphoid development. [11][12][13][14] In contrast, the role of Runx3 in hematopoiesis remains elusive, despite the fact that Runx3 is expressed in various hematopoietic tissues in adult mice.…”

Section: Introductionmentioning

confidence: 99%