Cooperating genes in inv(16) acute myeloid leukemia

超出所提供的空间。CBFB-MYH 11融合癌基因常见于急性髓性白血病（AML）。我们的长期目标是阐明决定CBFB-MYH 11介导的白血病进展的分子机制，以便为设计改进的疗法提供靶点。我们的一般假设是CBFB-MYH 11表达降低造血干细胞分化和增殖，并且协同突变影响与凋亡、增殖和存活相关的程序。我们已经确定Cbfb-MYH 11与其他突变协同诱导AML。我们已经建立了一个条件性小鼠模型，以显示融合基因的表达降低了造血祖细胞的分化和增殖能力，并在骨髓室中产生了白血病前体。此外，我们还鉴定了协同基因，并表明转录因子PlagL 2的组成型表达在Cbfb-MYH 11存在下扩增骨髓祖细胞并诱导AML。基于这些发现，本研究的具体目的是：（1）确定PlagL 2在造血祖细胞增殖和自我更新中的作用。我们将使用竞争性再增殖和系列移植测定来评估（a）PlagL 2损失和（B）组成性PlagL 2表达在长期造血干细胞中的作用。(2)明确PlagL 2在白血病进展中的作用机制。初步实验表明，PlagL 2诱导Mpl/Jak 2和TGF-β信号传导。我们将结合联合收割机体内和生物化学测定来确定PlagL 2在（a）Mpl/Jak 2和（B）TGF-β途径中功能的分子机制。(3)确定微小RNA在CBF/3SMMHC介导的急性髓性白血病中的作用。初步的遗传学证据表明，micro-RNA可以与Cbfb-MYH 11在白血病进展中协同作用。我们将使用体内测定来鉴定microRNA转化的机制。(4)确定Cbfb-MYH 11协同基因。我们将（a）扩大我们的遗传筛选，以识别和表征新的白血病基因，（B）确定在AML的发展中与Cbfb-MYH 11和PlagL 2协同作用的协同途径是否依赖于靶祖细胞群体。性能现场=

EXCEED THE SPACE PROVIDED. The CBFB-MYH11 fusion oncogene is frequently found in acute myeloid leukemia (AML). Our long term goal is to elucidate the molecular mechanisms that determine CBFB-MYH11-mediated leukemia progression in order to provide targets for the design of improved therapies. Our general hypothesis is that CBFB-MYH11 expression reduces hematopoietic stem cell differentiation and proliferation, and cooperating mutations affect programs associated with apoptosis, proliferation, and survival. We have determined that Cbfb-MYH11 induces AML in cooperation with other mutations. We have created a conditional mouse model to show that expression of the fusion gene reduced the differentiation and proliferation ability of hematopoietic progenitors and created leukemia precursors in the myeloid compartment. Furthermore, we have identified cooperating genes, and shown that constitutive expression of the transcription factor PlagL2 expanded myeloid progenitors and induced AML in the presence of Cbfb- MYH11.Based on these findings, the specific aims of this proposal are to: (1) determine PlagL2 role in proliferation and self-renewal of hematopoietic progenitors. We will use competitive repopulation and serial transplantation assays to assess the effect of (a) PlagL2-loss, and (b) constitutive PlagL2 expression, in long term-hematopoietic stem cells. (2) define the mechanism of PlagL2 function in leukemia progression. Preliminary experiments indicated that PlagL2 induces Mpl/Jak2 and TGF-beta signaling. We will combine in vivo and biochemical assays to determine the molecular mechanism of PlagL2 function in the (a) Mpl/Jak2 and (b) TGF-beta pathways. (3) determine the role of micro-RNAs in CBF/3SMMHC -mediated acute myeloid leukemia. Preliminary genetic evidence indicated that micro-RNAs can cooperate with Cbfb-MYH11 in leukemia progression. We will use in vivo assays to identify the mechanism of microRNA transformation. (4) Identify Cbfb-MYH11 cooperating genes. We will (a) expand our genetic screen to identify and characterize new leukemia genes, and (b) determine whether cooperating pathways that synergize with Cbfb-MYH11 and PlagL2 in the development of AML depend on the target progenitor population. PERFORMANCE SITE ========================================Section End===========================================