Bid Function in Myeloid Homeostasis and Leukemogenesis

BCL-2家族是细胞死亡途径中的一个重要关卡。BID是“BH3-Only”子集的成员之一 并需要其保守的BH3结构域来发挥其促凋亡功能。Bid在细胞凋亡途径中发挥重要作用 在死亡受体下游，如肿瘤坏死因子RI和Fas(1-7)。Caspase8的裂解和肉豆蔻酰化是一种激活 分子开关，便于Bid靶向线粒体(8)，在那里它激活多结构域促凋亡成员，如 如BAK或Bax，介导细胞色素c的释放和下游效应半胱氨酸天冬氨酸酶的激活(9)。Bid缺陷小鼠 活着并正常发育，但肝细胞对抗Fas诱导的肝细胞凋亡具有抵抗力(10)。因此出价 在某些类型的细胞中，在调节死亡受体下游的线粒体扩增环方面起着重要作用 肝细胞。然而，许多其他细胞，包括激活的淋巴细胞，在体外实验中被Fas杀死，直接激活 下游效应半胱氨酸天冬氨酸酶促进细胞凋亡(11)。然而，随着Bid缺陷小鼠年龄增长或受到慢性疾病的挑战 病毒感染后，我们发现在体内也需要Bid来维持所谓的I型细胞的动态平衡 包括B细胞、T细胞和单核细胞系(12)。随着Bid缺陷小鼠年龄的增加，它们表现为髓系增生和 继而进展为慢性粒-单核细胞白血病高发。创始家族成员BCL-2是在 滤泡性B细胞淋巴瘤的分子标志T(14：18)染色体断裂点建立了一类新的癌基因 其中的异常是细胞死亡而不是增殖(13-15)。在髓系细胞中过表达bcl2的转基因小鼠 发展成骨髓增殖性疾病，当与携带Fas受体突变的小鼠杂交时，进展为AML， 暗示Fas通路和Bcl2在抑制髓系肿瘤中的协同作用(16)。亲王的作用- 正常髓系动态平衡中的凋亡成员尚未得到很好的描述。我们认为，竞标是关键 在髓系中介导死亡受体信号的促凋亡中间体，其失活促进髓系 通过延长这些脆弱细胞的寿命，允许积累更多的突变，从而促进白血病的发生。这首单曲《BH3- 因此，只有“蛋白质”才有可能在维持正常的髓系稳态和肿瘤方面发挥重要作用。 压制。在此背景下，我提出了以下具体目标：1.明确Bid在髓系内稳态中的作用。2.定义 Bid在髓系白血病发生中的作用。3.确定与中标失败相关的二次基因变化 白血病的发生。

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.