MOLECULAR PATHOGENESIS OF CHROMOSOME 16 INVERSION INHUMA

16号染色体反转INHUMA的分子发病机制

• 批准号: 6681452
• 负责人: PU PAUL LIU
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6681452
• 关键词: acute myelogenous leukemia; carcinogenesis; chromosome inversion; disease /disorder model; fusion gene; hematopoiesis; human genetic material tag; human tissue; laboratory mouse; microarray technology; model design /development; molecular oncology; molecular pathology; neoplasm /cancer genetics; oncogenes; protein structure function; transcription factor; transfection; tumor suppressor genes

Chromosome 16 inversion is one of the most common chromosome abnormalities in human acute myeloid leukemia. A fusion gene between the core binding factor B (CBFB) gene and the myosin heavy chain 11 (MYH11) gene is generated by this inversion. Using transgenic mouse models we demonstrated previously that CBFB-MYH11 is necessary but not sufficient for leukemogenesis, and that additional genetic changes are needed for full leukemic transformation. We have since been able to identify such cooperating genetic changes in mice with a retroviral insertional mutagenesis approach. Knowledge of normal hematopoiesis will enhance our understanding of leukemogenic process. To understand the role of Cbfb in hematopoiesis and other developmental processes, mice with a Cbfb-GFP knock-in fusion have been generated. Using these mice we showed that Cbfb is expressed in the hematopoietic stem cells and is required for the function of such cells. These hematopoietic stem cells disappear in mice expressing CBFB-MYH11, indicating that the leukemic fusion gene blocks hematopoiesis at an early stage. Using the Cbfb-GFP mice we have also demonstrated that Cbfb plays an important role in bone development. There was a delayed bone formation in the Cbfb-GFP mice, similar to mice with impaired function of Runx2, a protein that interacts with Cbfb. Interestingly, mutations in the RUNX2 gene are responsible for a human genetic disease, cleiodo-cranial dysplasia (CCD), which is characterized by delayed bone formation. However, 20-35% of CCD patients do not have detectable mutations in their RUNX2 gene, raising the possibility that mutations in the CBFB gene might be responsible for some of those cases.

16号染色体倒位是人类急性髓性白血病中最常见的染色体异常之一。核心结合因子B （CBFB）基因与肌球蛋白重链11 （MYH11）基因通过这种反转产生融合基因。利用转基因小鼠模型，我们先前证明了CBFB-MYH11对于白血病的发生是必要的，但不是充分的，并且需要额外的遗传改变才能完全转化白血病。我们已经能够用逆转录病毒插入诱变方法在小鼠中识别出这种合作的遗传变化。正常造血的知识将增强我们对白血病发生过程的理解。为了了解Cbfb在造血和其他发育过程中的作用，已经产生了Cbfb- gfp敲入融合的小鼠。利用这些小鼠，我们发现Cbfb在造血干细胞中表达，并且是造血干细胞功能所必需的。这些造血干细胞在表达CBFB-MYH11的小鼠中消失，表明白血病融合基因在早期阻断了造血。使用Cbfb- gfp小鼠，我们也证明了Cbfb在骨发育中起重要作用。Cbfb- gfp小鼠的骨形成延迟，类似于Runx2功能受损的小鼠，Runx2是一种与Cbfb相互作用的蛋白质。有趣的是，RUNX2基因的突变与人类遗传性疾病锁骨-颅骨发育不良（CCD）有关，其特征是骨形成延迟。然而，20-35%的CCD患者的RUNX2基因没有可检测到的突变，这增加了CBFB基因突变可能导致其中一些病例的可能性。