Loss of AML1/Runx1 accelerates the development of MLL-ENL leukemia through down-regulation of p19(ARF)

Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Blood (Impact Factor: 10.45). 07/2011; 118(9):2541-50. DOI: 10.1182/blood-2010-10-315440
Source: PubMed


Dysfunction of AML1/Runx1, a transcription factor, plays a crucial role in the development of many types of leukemia. Additional events are often required for AML1 dysfunction to induce full-blown leukemia; however, a mechanistic basis of their cooperation is still elusive. Here, we investigated the effect of AML1 deficiency on the development of MLL-ENL leukemia in mice. Aml1 excised bone marrow cells lead to MLL-ENL leukemia with shorter duration than Aml1 intact cells in vivo. Although the number of MLL-ENL leukemia-initiating cells is not affected by loss of AML1, the proliferation of leukemic cells is enhanced in Aml1-excised MLL-ENL leukemic mice. We found that the enhanced proliferation is the result of repression of p19(ARF) that is directly regulated by AML1 in MLL-ENL leukemic cells. We also found that down-regulation of p19(ARF) induces the accelerated onset of MLL-ENL leukemia, suggesting that p19(ARF) is a major target of AML1 in MLL-ENL leukemia. These results provide a new insight into a role for AML1 in the progression of leukemia.

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    • "Immature haematopoietic progenitors of FDP/AML patients have increased clonogenic potential and, in some cases, aberrant self-renewal capacities (Bluteau et al, 2011). Consistently, Runx1 conditional knockout mice presented expansion of haematopoietic stem cells that could predispose to leukaemia development (Nishimoto et al, 2011). Mks cultured from CD34 + cells of FDP/AML subjects were characterized by profound defects in maturation to glycoprotein (GP)IIb+/GPIX+ cells and in polyploidization. "
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