MLL FUSION GENES IN MYELOID AND LYMPHOID LEUKEMIAS

在11 q23处携带染色体易位的急性白血病具有混合谱系白血病基因（MLL、HRX、ALL-1）的重排。已经报道了超过40种不同的MLL易位，但t（9;11）（MLL-AF 9）和t（4;11）（MLL-AF 4）特别常见。MLL-AF 9最常在诊断为AML的白血病中鉴定，而MLL-AF 4仅在诊断为ALL或混合谱系白血病的白血病中发现。MLL-AF 4重排白血病患者预后不良。对于婴儿白血病尤其如此，其中大约80%的病例将具有MLL重排 基因我们以前已经证明，人类淋巴母细胞白血病窝藏MLL重排具有独特的基因表达谱，这表明他们来自早期造血祖细胞。这种方法还确定了受体酪氨酸激酶FLT 3作为这种疾病的潜在治疗靶点。使用MLL-AF 9诱导的AML的鼠模型系统，我们最近已经鉴定了在粒细胞巨噬细胞祖细胞（GMP）转化为白血病干细胞（LSC）期间在其中激活的造血干细胞（HSC）相关基因表达程序。在这些研究中，我们注意到cebp/a的抑制是MLL-AF 9诱导程序的一个组成部分。在具体目标1中，我们将评估在LSC中高度表达的特定基因，并进行高通量筛选以鉴定逆转LSC程序的小分子。在本提案的具体目标2中，我们将与项目3的成员合作，探讨cebp/a在MLL重排白血病中的作用。在具体目标3中，我们将与项目1和2的成员合作，开发MLL-AF 4诱导白血病的条件性小鼠模型，并评估白血病发生过程中与突变型FLT 3等位基因合作的潜力。这样的模型不仅可以识别对MLL-AF 4诱导的转化敏感的祖细胞群体，而且还为评估项目1和2中开发的疗法提供了急需的模型。

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(9;11) (MLL-AF9) and the t(4;11) (MLL-AF4) are particularly common. MLL-AF9 is most frequently identified in leukemias diagnosed as AML whereas MLL-AF4 is found solely in leukemias diagnosed as ALL or mixed-lineage leukemia. Patients with MLL-AF4 rearranged 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 previously demonstrated that human lymphoblastic leukemias harboring MLL-rearrangements possess a unique gene expression profile that suggests they arise from an early hematopoietic progenitor. This approach also identified the receptor tyrosine kinase FLT3 as a potential therapeutic target in this disease. Using a murine model system of MLL-AF9 induced AML, we have recently identified a hematopoietic stem cell (HSC) associated gene expression program activated in granulocyte macrophage progenitors (GMP) during their conversion to leukemia stem cells (LSC). In these studies we noted repression of cebp/a as a component of the MLL-AF9 induced program. In specific aim 1 we will asses specific genes found highly expressed in LSC, and perform a high-throughput screen to identify small molecules that reverse the LSC program. In specific aim 2 of this proposal we will work with members of project 3 to interrogate the role of cebp/a in MLL-rearranged leukemia. In specific aim 3 we will work with members of projects 1 and 2 to develop a conditional murine model of MLL-AF4 induced leukemia and assess the potential for cooperation with mutant FLT3 alleles during leukemogenesis. Such a model will not only allow identification of progenitor populations susceptible to MLL-AF4 induced transformation, but also provide a much-needed model for assessment of therapeutics developed in projects 1 and 2.