MLL AF4 Leukemia

描述（由申请人提供）：长期以来，已知人类MLL-AF 4白血病具有独特的生物学特征，具有淋巴或混合谱系表型，婴儿发病率高，预后差。 这次全面更新的总体目标是扩大我们过去20年的研究，旨在了解MLL-AF 4白血病独特的分子和细胞病理学。重点将放在我们的新MII-AF 4敲入小鼠模型最近在Kersey实验室开发的技术进步，在过去的四年。MLL融合基因白血病的敲入模型具有融合基因在生理启动子的控制下表达的优点，并且如在人白血病中一样具有MLL的单倍不足。据我们所知，这是第一个MLL-AF 4模型，其证明了体外和体内淋巴样区室的扩增以及最终的白血病。这是重要的，因为人MLL-AF 4白血病在淋巴区室中发展。相比之下，MLL-AF 9导致髓样区室扩增和髓样白血病;人MLL-AF 9白血病通常是髓样的。这些结果与MLL伴侣基因在确定最终白血病表型中的主动和指导性（而不是被动）作用一致。在下一个资助期，我们的具体目标是针对详细的机制研究，询问主要的造血祖细胞和干细胞群体，以了解MLL融合伴侣（AF 4或AF 9）在这种选择性扩增中的这种活性和指导性作用的细胞基础。迄今为止，MLL-AF 4小鼠仅在5个月后发生白血病，并且有点出乎意料地是骨髓单核细胞而不是淋巴细胞类型。在与大卫Largaespada博士合作，我们将致力于开发一个完全渗透模型MLL-AF 4启动淋巴细胞白血病。在这些研究中，我们将评估合作突变，包括FLT 3和END或新型MuLV逆转录病毒诱导的突变。将评估AF 4单倍不足在MLL-AF 4淋巴细胞白血病发展中的可能作用。我们的初步数据表明，51个HOXA簇基因作为MLL融合基因的靶标发挥重要作用。在此期间，我们将对MLL-AF 4和MLL-AF 9小鼠的祖细胞和干细胞群中的51个HOX A簇和MEIS 1基因进行详细研究。将考虑HOXA簇、MEIS 1或MLL融合基因作为潜在的治疗靶点。

DESCRIPTION (provided by applicant): MLL-AF4 leukemia in humans has long been known to have a unique and distinctive biology with a lymphoid or mixed lineage phenotype, high incidence in infants and a poor prognosis. The overall goal of this completive renewal is to expand our studies of the last 20 years that are designed to understand the unique molecular and cellular pathobiology of MLL-AF4 leukemia. Emphasis will be on our novel MII-AF4 knock in murine model developed recently in the Kersey laboratory as a result of technical advances over the past four years. Knock in models of MLL fusion gene leukemia have the advantage of expression of the fusion gene under control of the physiologic promoter and haploinsufficiency of MLL as in human leukemia To our knowledge this is the first MLL-AF4 model demonstrating an expansion of the lymphoid compartment in vitro and in vivo and eventual leukemia. This is significant because human MLL-AF4 leukemia develops within the lymphoid compartment. In contrast MLL-AF9 results in myeloid compartment expansion and myeloid leukemia; Human MLL-AF9 leukemia is generally myeloid. These results are consistent with an active and instructive (rather than a passive) role for the MLL partner gene in determination of the eventual leukemia phenotype. In the next grant period our specific aims are directed at detailed mechanistic studies interrogating the major hematopoietic progenitor and stem cell populations to understand the cellular basis for this active and instructive role of the MLL fusion partner (AF4 or AF9) in this selective expansion The MLL-AF4 mice to date have developed leukemia only after 5 months and somewhat unexpectedly have been myelomonocytic rather than lymphoid in type. In collaboration with Dr. David Largaespada we will work to develop a fully penetrant model of MLL-AF4 initiated lymphoid leukemia. In these studies we will evaluate cooperating mutations including FLT3 and mutations induced by END or a novel MuLV retrovirus. The possible role of haploinsufficiency of AF4 in the development of MLL-AF4 lymphoid leukemia will be evaluated. Our preliminary data indicate that 51 HOX A cluster genes play a significant role as targets for MLL fusion genes. In this grant period we will conduct detailed studies of 51 HOX A cluster and MEIS1 genes in the progenitor and stem cell populations in both MLL-AF4 and MLL-AF9 mice. Consideration will be given to HOXA cluster, MEIS1 or MLL fusion genes as potential therapeutic targets.