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[Familial leukemia due to germline RUNX1 mutations: lessons learned from two decades of research and unsolved problems].

The RUNX1 gene is a critical transcription factor for the generation and maintenance of hematopoietic stem cells. RUNX1 is also one of the most frequently mutated gene in sporadic leukemias. Heterozygous loss-of-function mutations of the RUNX1 gene in the germline cause a rare autosomal dominant disorder called familial platelet disorder with propensity to acute myelogenous leukemia (FPD/AML). Besides the preexisting platelet disorder in FPD/AML patients, AML also develops in 20-60% of affected individuals. Since its discovery by the Gilliland group in 1999, RUNX1 mutation in the germline has been extensively investigated in the field. The past two decades of research have taught us three important lessons: 1) patients with FPD/AML display atypical symptoms and they have a widened clinical spectrum of FPD, such as eczema and syndromic thrombocytopenia, 2) the elucidation of variant of uncertain significance (VUS) of RUNX1 have revealed their role in epigenetic functions and involvement in the Fanconi anemia DNA repair pathway, and 3) non-coding mutations of RUNX1 also causes FPD/AML. In three distinct familial cases, an enhancer for RUNX1, eR1, was either lost or disconnected from the promoter through genetic deletion or chromosomal translocation abnormalities. This experience, with congenital mutations of RUNX1, will be very useful for future research for a series of other leukemia-causing germline mutations that have been recently identified.