Point mutations of the RUNX1/AML1 gene in sporadic and familial myeloid leukemias
Point mutations of the RUNX1/AML1 gene in sporadic and familial myeloid leukemias
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DOI：
10.1007/bf02982056
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发表时间：
2001-10-01
影响因子：
2.1
通讯作者：
Ito, Y
中科院分区：
文献类型：
--
作者：
Osato, M;Yanagida, M;Ito, Y
已知RUNX1/AML1基因是白血病中染色体易位最常见的靶标。此外，最近的研究表明，RUNX1基因的点突变是导致白血病的另一种遗传病变模式。特别有趣的是，双等位基因型的散发性点突变被发现与急性髓性白血病（AML） MO亚型或21三体密切相关。种系突变引起家族性血小板疾病，导致急性髓性白血病（FPD/AML）的易感性。大多数RUNX1突变体在DNA结合上存在缺陷，但在β结合上仍然活跃，这一特征与三维结构的发现一致，可能解释了主要的抑制作用。虽然在某些情况下观察到RUNX1的真正单倍性不足，但大多数突变的RUNX1蛋白也可能以显性负性方式起作用，可能导致白血病发展的更高倾向。这种较强的显性负向效应也被推断为染色体易位产生嵌合基因的主要机制。RUNX1活性的降低可能是RUNX1相关白血病的常见潜在原因。然而，由于这些RUNX1异常本身不足以导致白血病的发生，因此应该集中寻找合作的遗传改变，以进一步了解机制和未来的临床应用。(C) 2001日本血液病学会。
The RUNX1/AML1 gene is known to be the most frequent target for chromosomal translocation in leukemia. In addition, recent studies have demonstrated point mutations in the RUNX1 gene as an another mode of genetic lesion resulting in leukemia. Of particular interest, sporadic point mutations of biallelic type are found in a tight association with either the acute myelogenous leukemia (AML) MO subtype or trisomy 21. Germline mutations give rise to a familial platelet disorder that results in a predisposition to acute myelogenous leukemia (FPD/AML). Most of the RUNX1 mutants were defective in DNA binding but still active in beta binding, a characteristic that is consistent with the 3-dimensional structural findings and may explain the dominant inhibitory effects. Although genuine haploinsufficiency of RUNX1 was observed in some cases, a greater majority of mutant RUNX1 proteins may also act in a dominant-negative manner, possibly creating a higher propensity for leukemia development. The stronger dominant-negative effect was also deduced to be the major mechanism of the chimeric genes created by chromosomal translocations. The decrement of RUNX1 activity may be a common underlying cause for RUNX1-related leukemias. However, because these RUNX1 abnormalities per se are insufficient for leukemogenesis, cooperating genetic alteration(s) should be intensively sought for further mechanistic insights and future clinical applications. (C) 2001 The Japanese Society of Hematology.