Matheny Christina J, Speck Maren E, Cushing Patrick R, Zhou Yunpeng, Corpora Takeshi, Regan Michael, Newman Miki, Roudaia Liya, Speck Caroline L, Gu Ting-Lei, Griffey Stephen M, Bushweller John H, Speck Nancy A
Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755, USA.
EMBO J. 2007 Feb 21;26(4):1163-75. doi: 10.1038/sj.emboj.7601568. Epub 2007 Feb 8.
Monoallelic RUNX1 mutations cause familial platelet disorder with predisposition for acute myelogenous leukemia (FPD/AML). Sporadic mono- and biallelic mutations are found at high frequencies in AML M0, in radiation-associated and therapy-related myelodysplastic syndrome and AML, and in isolated cases of AML M2, M5a, M3 relapse, and chronic myelogenous leukemia in blast phase. Mutations in RUNX2 cause the inherited skeletal disorder cleidocranial dysplasia (CCD). Most hematopoietic missense mutations in Runx1 involve DNA-contacting residues in the Runt domain, whereas the majority of CCD mutations in Runx2 are predicted to impair CBFbeta binding or the Runt domain structure. We introduced different classes of missense mutations into Runx1 and characterized their effects on DNA and CBFbeta binding by the Runt domain, and on Runx1 function in vivo. Mutations involving DNA-contacting residues severely inactivate Runx1 function, whereas mutations that affect CBFbeta binding but not DNA binding result in hypomorphic alleles. We conclude that hypomorphic RUNX2 alleles can cause CCD, whereas hematopoietic disease requires more severely inactivating RUNX1 mutations.
单等位基因RUNX1突变导致家族性血小板疾病并易患急性髓性白血病（FPD/AML）。在AML M0、辐射相关和治疗相关的骨髓增生异常综合征及AML中，以及在AML M2、M5a、M3复发和急变期慢性髓性白血病的个别病例中，散发性单等位基因和双等位基因突变的出现频率很高。RUNX2突变导致遗传性骨骼疾病锁骨颅骨发育不全（CCD）。Runx1中的大多数造血错义突变涉及Runt结构域中与DNA结合的残基，而Runx2中的大多数CCD突变预计会损害CBFβ结合或Runt结构域结构。我们将不同类型的错义突变引入Runx1，并通过Runt结构域对其对DNA和CBFβ结合以及Runx1体内功能的影响进行了表征。涉及与DNA结合残基的突变会严重使Runx1功能失活，而影响CBFβ结合但不影响DNA结合的突变会导致亚效等位基因。我们得出结论，亚效RUNX2等位基因可导致CCD，而造血疾病需要更严重的使RUNX1失活突变。
