Molecular pathogenesis of MLL-AF4 leukemias

描述(申请人提供)：带有11q23染色体易位的急性白血病具有混合血统白血病基因(MLL，HRX，ALL-1)的重排。已经报道了40多种不同的MLL易位，但t(4；11)(MLL-AF4)在被诊断为ALL或混合系白血病的白血病中尤其常见。MLL-AF4白血病患者预后较差。这对于婴儿白血病尤其如此，大约80%的病例将携带MLL基因重排。我们最近建立了MLL-AF4 ALL的条件性小鼠模型，它概括了人类MLL-AF4 ALL的基因表达谱和组蛋白甲基化谱。本提案中描述的实验将建立在这些先前研究的基础上，并以组蛋白甲基化为重点来表征白血病的发展。我们将确定哪些细胞类型允许发生MLL-AF4白血病，包括造血干细胞(HSC)和早期淋巴样承诺细胞。我们还将确定MLL-AF4白血病细胞的存活是否依赖于组蛋白甲基转移酶DOT1L。这些研究将提供MLL-AF4 ALL起源细胞的高度详细的特征，并开始确定组蛋白甲基转移酶是否为该疾病的潜在治疗靶点。

DESCRIPTION (provided by applicant): Acute leukemias that bear chromosomal translocations at 11q23 possess rearrangements of the Mixed Lineage Leukemia gene (MLL, HRX, ALL-1). More than 40 different MLL translocations have been reported, but the t(4;11) (MLL-AF4) is particularly common in leukemias diagnosed as ALL or mixed-lineage leukemia. Patients with MLL-AF4 leukemias have a poor prognosis. This is particularly true for infant leukemia where approximately 80% of cases will harbor rearrangement of the MLL gene. We have recently developed a conditional mouse model of Mll-AF4 ALL that recapitulates the gene expression profiles and histone methylation profiles of human MLL-AF4 ALL. Experiments described in this proposal will build upon these previous studies and characterize leukemia development with a particular focus on histone methylation. We will determine which cell types are permissive for Mll-AF4 leukemia development including hematopoietic stem cells (HSC) and early lymphoid committed cells. We will also determine if MLL-AF4 leukemia cell survival is dependent upon the histone methyltransferase Dot1L. These studies will provide a highly detailed characterization of the cells of origin of Mll-AF4 ALL, and begin to determine if histone methyltransferases are potential therapeutic targets in this disease.