Bid Function in Myeloid Homeostasis and Leukemogenesis

Bid 在骨髓稳态和白血病发生中的功能

• 批准号: 6952025
• 负责人: Sandra S Zinkel
• 金额: $ 13.03万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952025
• 关键词: BCL2 gene /protein; apoptosis; biological signal transduction; carcinogenesis; comparative genomic hybridization; cytogenetics; flow cytometry; fluorescent in situ hybridization; genetically modified animals; histology; laboratory mouse; leukemia; myeloid stem cell; polymerase chain reaction; protein structure function; BCL2 gene /protein; apoptosis; biological signal transduction; carcinogenesis; comparative genomic hybridization; cytogenetics; flow cytometry; fluorescent in situ hybridization; genetically modified animals; histology; laboratory mouse; leukemia; myeloid stem cell; polymerase chain reaction; protein structure function

DESCRIPTION (provided by applicant): 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 of pro-apoptotic members in normal myeloid homeostasis has not been well characterized. We propose that BID is the critical proapoptotic intermediate that mediates death receptor signaling 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.

描述（由申请人提供）：BCL-2家族在细胞死亡途径中构成了关键检查点。竞标是该家族的“仅BH3”子集的成员，并要求其保守的BH3域才能促凋亡。投标在死亡受体（例如TNF RI和FAS）下游的凋亡途径中起重要作用（1-7）。 caspase 8和肉豆蔻酰化的裂解是一种激活的分子开关，可促进靶向竞标到线粒体（8），在该靶向线粒体（8）中，它激活了多域的促凋亡构件，例如bak或bax，例如介导细胞色素C的释放和下降效应效应的caspases caspases的释放（9）。缺乏投标的小鼠是可行的，并且正常发育，但是肝细胞对抗FAS诱导的肝细胞凋亡具有抗性（10）。因此，投标在介导某些细胞类型（例如肝细胞）下下游的线粒体扩增环中起着重要作用。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，直接激活下游效应子caspases以促进细胞凋亡（11）。但是，随着竞标不足的小鼠的年龄或受到慢性病毒感染的挑战，我们发现在体内也需要单一的竞标来维持在包括B细胞，T细胞和骨髓细胞细胞的所谓I型细胞中的稳态（12）。随着竞标不足的小鼠的年龄，它们表现出髓样增生，然后在高发病率的情况下发展为慢性骨髓细胞性白血病。创始家族成员Bcl-2在T（14:18）染色体断裂点上克隆，这是卵泡B细胞淋巴瘤的分子标志，建立了一类新的Oncogenes，其中像差为细胞死亡，而不是增殖而不是增殖（13-15）。转基因小鼠在髓样细胞中表达Bcl-2的转基因小鼠会出现髓增生性疾病，当与携带FAS受体突变的小鼠交叉时，AML发展为AML，暗示了FAS途径和Bcl-2在骨髓统计抑制肿瘤中的协同作用（16）。促凋亡成员在正常髓样稳态中的作用尚未得到很好的特征。我们建议竞标是介导髓样谱系中死亡受体信号传导的关键促凋亡中间体，其失活通过延长这些脆弱细胞的寿命，从而促进髓样白血病生成，从而促进这些脆弱的细胞的寿命，从而积累其他突变。因此，这种单一的“仅BH3”蛋白具有在维持正常髓样稳态和抑制肿瘤方面发挥有效作用的潜力。在这种情况下，我提出以下特定目的：1。定义出价在髓样稳态中的作用。 2。定义出价在髓样白血病发生中的作用。 3。确定与白血病中出价损失合作的二次遗传变化。