GATA2 monoallelic expression underlies reduced penetrance in inherited GATA2-mutated MDS/AML

Abstract

While the majority of myelodysplasia and acute myeloid leukemia (MDS/AML) cases are sporadic, rare familial predisposition syndromes have been delineated and now represent a separate disease entity in the revised World Health Organization (WHO) classification of myeloid neoplasms [ 1 ]. Germline mutations in ~14 disease genes have been uncovered thus far, with GATA2 representing one of the key transcriptional regulators commonly mutated in inherited MDS/AML [ 2 ]. Increasing evidence suggests that aberrations in GATA2 impair its transcription and promoter activation, leading to a loss-of-function, supporting a mechanism of GATA2 haploinsufficiency [ 3 , 4 , 5 ]. Reduced penetrance, the observation that family members carry an identical germline mutation yet display variable clinical manifestations, is common and poses a clinical challenge in the diagnosis and management of familial leukemia's, particularly when identifying “silent” mutation carriers for genetic screening and exclusion as potential stem cell transplant donors [ 6 , 7 ]. Indeed, we have noted that reduced penetrance is a feature among certain GATA2 -mutated MDS/AML families [ 8 ], especially those harboring missense germline mutations such as c.1061C>T (p.Thr354Met) (Table S1 ) although the precise molecular explanation of such occurrence has not been investigated.