Mechanisms of leukemogenesis caused by alterations of the structure of transcription factor PEBP2

转录因子PEBP 2由α和β亚基组成。RUNX 1/AML 1、RUNX 2/CBFA 1、RUNX 3/PEBP 2 αC是内皮细胞向造血干细胞分化的关键基因。RUNX 1是与急性白血病相关的染色体易位的最常见靶点，但我们发现了不涉及嵌合蛋白的零星功能丧失点突变。后来，报告了点突变的家族性病例，称为家族性髌骨疾病伴急性髓性白血病易感性（FPD-AML）。RUNX 1基因突变的小鼠是FPD-AML的良好模型，RUNX 1单倍不足与白血病的发生有关，RUNX 2基因突变对软骨细胞和成骨细胞的成熟至关重要。RUNX 2的单倍不足导致锁骨颅骨发育不良（CCD）。我们发现RUNX 2是TGF-β/BMP信号通路的主要靶点之一，RUNX 2基因突变后破坏BMP信号通路导致CCD的发生，RUNX 3基因在胃肠道上皮细胞中表达，RUNX 3基因突变后引起腺胃上皮细胞增生。RUNX 3在胃癌中的可能参与正在研究中。

Transcription factor PEBP2 is composed of α and β subunits. There are three genes encoding the α subunit, RUNX1/AML1, RUNX2/CBFA1, RUNX3/PEBP2αC.We found that RUNX1 is required for generation of hematopoietic stem cells from endothelial cells. RUNX1 is the most frequent target of chromosome translocations associated with acute leukemia but we found sporadic loss-of-function point mutations without involving chimeric proteins. Later, familial cases of point mutations were reported which are called Familial Patelet Disorder with Predisposition to Acute Myeloid Leukemia (FPD-AML). Mice carrying heterozygously disrupted RUNX1 gene were found to be a good mouse model for FPD-AML.Haploinsufficiency of RUNX1 is being proved to be leukemogenic.RUNX2 is essential for maturation of chondrocytes and osteoblasts. Haploinsufficiency of RUNX2 causes cleidocranial dysplasia (CCD). We found that RUNX2 is one of the major target of TGF-β/BMP signaling and mutations of RUNX2 impaired the BMP pathway to cause CCD.We found that RUNX3 was expressed in epithelial cells of gastrointestinal tractand that the disruption of the gene caused hyperplasia of epithelial layer of glandular stomach. Possible involvement of RUNX3 in gastric cancer is being studied.