MLL AF4 Leukemia

描述(申请人提供)：人类MLL-AF4白血病具有独特和独特的生物学特征，具有淋巴或混合血统表型，在婴儿中发病率高，预后不良。这次完整更新的总体目标是扩大我们过去20年的研究，旨在了解MLL-AF4白血病独特的分子和细胞病理生物学。重点将放在我们最近在Kersey实验室开发的新型MII-AF4敲入小鼠模型上，这是过去四年技术进步的结果。敲入MLL融合基因白血病模型具有在生理启动子控制下融合基因的表达和MLL单倍体不足的优点，据我们所知，这是第一个证明淋巴室在体外和体内扩张并最终导致白血病的MLL-AF4模型。这一点意义重大，因为人类MLL-AF4白血病发生在淋巴间隔内。相反，MLL-AF9导致髓系室扩大和髓系白血病；人类MLL-AF9白血病通常是髓系白血病。这些结果与MLL伙伴基因在确定最终白血病表型中的积极和指导作用(而不是被动作用)是一致的。在下一个授权期，我们的具体目标是进行详细的机制研究，询问主要的造血祖细胞和干细胞群体，以了解MLL融合伙伴(AF4或AF9)在这种选择性扩增中发挥积极和指导作用的细胞基础。迄今为止，MLL-AF4小鼠在5个月后才出现白血病，有些出人意料地是粒单核细胞型而不是淋巴细胞型。与David Largespada博士合作，我们将致力于开发MLL-AF4启动的淋巴细胞性白血病的全渗透模型。在这些研究中，我们将评估包括Flt3在内的协同突变以及END或一种新的MuLV逆转录病毒诱导的突变。将评估AF4单倍体不足在MLL-AF4淋巴细胞性白血病发生中的可能作用。我们的初步数据表明，51个Hox A簇基因作为MLL融合基因的靶点发挥了重要作用。在这一资助期间，我们将对MLL-AF4和MLL-AF9小鼠的祖细胞和干细胞群体中的51个Hox A簇和Meis1基因进行详细研究。HoxA簇、Meis1或MLL融合基因将被考虑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.