Bid Function in Myeloid Homeostasis and Leukemogenesis

BCL-2家族构成细胞死亡途径中的关键检查点。BID是本发明的“仅BH 3”子集的成员。 家族，并且需要其保守的BH 3结构域用于其促凋亡功能。BID在凋亡途径中起重要作用 死亡受体如TNF RI和Fas的下游（1-7）。半胱天冬酶8和豆蔻酰化的切割作为激活 分子开关，其促进BID靶向线粒体（8），在线粒体中其激活多结构域促凋亡成员， 如巴克或BAX，介导细胞色素c的释放和下游效应物半胱天冬酶的激活（9）。Bid缺陷小鼠 存活并正常发育，然而肝细胞对抗Fas诱导的肝细胞凋亡具有抗性（10）。因此， 在某些细胞类型中， 肝细胞然而，许多其他细胞，包括活化的淋巴细胞，在体外测定中被Fas杀死，直接活化 下游效应物半胱天冬酶促进细胞凋亡（11）。然而，随着Bid缺陷小鼠年龄的增长或受到慢性 病毒感染时，我们发现BID在体内也是维持所谓I型细胞内稳态所必需的 包括B细胞、T细胞和骨髓单核细胞谱系（12）。随着Bid缺陷小鼠年龄的增长，它们表现出骨髓增生， 然后进展为慢性粒单核细胞白血病，发病率很高。家族的创始成员BCL-2是在1999年克隆的。 t（14：18）染色体断裂点，滤泡性B细胞淋巴瘤的分子标志，在淋巴瘤中建立了一类新的癌基因。 其中畸变是在细胞死亡而不是增殖中（13-15）。骨髓细胞中BCL-2过表达的转基因小鼠 发生骨髓增生性疾病，当与Fas受体突变的小鼠杂交时，进展为AML， 暗示Fas途径和Bcl-2在髓系肿瘤抑制中的协同作用（16）。亲的作用- 正常骨髓内稳态中的凋亡成员还没有得到很好的表征。我们建议，BID是关键的 在髓系中介导死亡受体信号传导的促凋亡中间体，其失活促进髓系 通过延长这些脆弱细胞的寿命，允许额外突变的积累，从而促进白血病的发生。这首单曲“BH 3- 因此，只有”蛋白质“才有可能在维持正常骨髓内稳态以及肿瘤中发挥有效作用。 镇压在这方面，我提出以下具体目标：1。明确Bid在骨髓稳态中的作用。2.定义 Bid在髓系白血病发生中的作用。3.确定与Bid丢失合作的继发性遗传变化， 白血病发生

The BCL-2 family constitutes a crucial checkpoint in the cell death pathway. BID is a member of the "BH3-only" subset of this family and requires its conserved BH3 domain for its pro-apoptotic function. BID plays an important role in the apoptotic pathway downstream of death receptors such as TNF RI and Fas (1-7). Cleavage by caspase 8 and myristoylation serves as an activating molecular switch which facilitates targeting of BID to mitochondria(8) where it activates multidomain proapoptotic members such as BAK or BAX, mediating the release of cytochrome c and activation of downstream effector caspases (9). Bid-deficient mice are viable and develop normally, however hepatocytes are resistant to anti-Fas-induced hepatocellular apoptosis(10). BID thus plays an important role in mediating a mitochondrial amplification loop downstream of death receptors in certain cell types such as hepatocytes. Yet many other cells, including activated lymphocytes, are killed by Fas in in vitro assays, directly activating downstream effector caspases for the promotion of apoptosis(11). However, as Bid-deficient mice age or are challenged by chronic viral infection, we've discovered that BID is also singularly required in vivo to maintain homeostasis in so-called Type I cells including B cells, T cells, and the myelomonocytic lineage(12).As Bid-deficient mice age, they display a myeloid hyperplasia and then progress to Chronic myelomonocytic leukemia at high incidence. The founding family member, BCL-2 was cloned at the t(14:18) chromosomal breakpoint, the molecular hallmark of follicular B cell lymphoma establishing a new class of oncogenes in which the aberration is in cell death rather than proliferation(13-15). Transgenic mice over expressing BCL-2 in myeloid cells develop a myeloproliferative disorder, and when crossed with mice harboring a mutation in the Fas receptor, progress to AML, implicating a synergistic role for the Fas pathway and Bcl-2 in tumor suppression of the myeloid lineage(16). The role ofpro- apoptotic members in normal myeloid homeostasis has not been well characterized. We propose that BID is the critical proapoptotic intermediate that mediates death receptor signalling in the myeloid lineage and that its inactivations promotes myeloid leukemogenesis by prolonging the life of these vulnerable cells, allowing accumulation of additional mutations. This single "BH3- only" protein therefore has potential to play a potent role in maintenance of normal myeloid homeostasis as well as tumor suppression. In this context, I propose the following specific aims: 1. Define the role of Bid in myeloid homeostasis. 2. Define the role of Bid in myeloid leukemogenesis. 3. Identify the secondary genetic changes that cooperate with loss of Bid in leukemogenesis.