Cooperating genes in inv (16) acute myeloid leukemia

描述（由申请人提供）：CBFB-MYH11融合癌基因常见于急性髓系白血病（AML）中。我们的长期目标是阐明决定 CBFB-MYH11 介导的白血病进展的分子机制，以便为改进疗法的设计提供目标。我们的一般假设是 CBFB-MYH11 表达减少造血干细胞分化和增殖，并且协同突变影响与增殖和存活相关的程序。我们已经确定 Cbfb-MYH11 与其他突变协同诱导 AML。我们创建了一个条件小鼠模型，以表明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，例如转录因子 Plag1 和 PlagL2 以及 microRNA 簇 miR17-92，并表明转录因子 PlagL2 的组成型表达可在 Cbfb-MYH11 存在的情况下扩增骨髓祖细胞并诱导 AML。基于这些发现，本提案的具体目标是：（1）确定PlagL2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连续移植测定来评估 (a) PlagL2 缺失和 (b) 组成型 PlagL2 表达对长期造血干细胞的影响。 (2)明确PlagL2在白血病进展中的作用机制。初步实验表明 PlagL2 诱导 Mpl/Jak2 和 TGF-β 信号传导。我们将结合体内和生化测定来确定 PlagL2 在 (a) Mpl/Jak2 和 (b) TGF-β 途径中功能的分子机制。此外，我们将测试Plag表达是否是维持白血病所必需的。 (3)确定微小RNA在CBF-SMMHC介导的急性髓系白血病中的作用。初步遗传学证据表明，micro-RNA 可以与 Cbfb-MYH11 协同参与白血病进展。我们将使用体内测定来确定 microRNA 转化的机制。

DESCRIPTION (provided by applicant): 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 that cooperating mutations affect programs associated with 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, such as the transcription factors Plag1 and PlagL2 and the microRNA cluster miR17-92, 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. In addition, we will test whether Plag expression is necessary for maintenance of leukemia. (3) determine the role of micro-RNAs in CBF-SMMHC -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.