Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation.
Inherited or sporadic heterozygous mutations in the transcription factor GATA2 lead to a clinical syndrome characterized by non-tuberculous mycobacterial and other opportunistic infections, a severe deficiency in monocytes, B cells and natural killer cells, and progression from a hypocellular myelodysplastic syndrome to myeloid leukemias. To identify acquired somatic mutations associated with myeloid transformation in patients with GATA2 mutations, we sequenced the region of the ASXL1 gene previously associated with transformation from myelodysplasia to myeloid leukemia. Somatic, heterozygous ASXL1 mutations were identified in 14/48 (29%) of patients with GATA2 deficiency, including four out of five patients who developed a proliferative chronic myelomonocytic leukemia. Although patients with GATA2 mutations had a similarly high incidence of myeloid transformation when compared to previously described patients with ASXL1 mutations, GATA2 deficiency patients with acquired ASXL1 mutation were considerably younger, almost exclusively female, and had a high incidence of transformation to a proliferative chronic myelomonocytic leukemia. These patients may benefit from allogeneic hematopoietic stem cell transplantation before the development of acute myeloid leukemia or chronic myelomonocytic leukemia. (ClinicalTrials.gov identifier NCT00018044, NCT00404560, NCT00001467, NCT00923364.).
westrob@mail.nih.gov.
Robert R
RR
West
Amy P
AP
Hsu
Steven M
SM
Holland
Jennifer
J
Cuellar-Rodriguez
Dennis D
DD
Hickstein
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D005260:Female; D050989:GATA2 Transcription Factor / Q000235:genetics*; D006801:Humans; D015994:Incidence; D015477:Leukemia, Myelomonocytic, Chronic / Q000453:epidemiology / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D012737:Sex Factors
C473949:ASXL1 protein, human; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D009363:Neoplasm Proteins; D012097:Repressor Proteins