DDX41 represents a class of tumor suppressor genes in myeloid neoplasms
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Somatic missense mutations in DDX41 can be found in AML
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Germline DDX41 mutations predispose to somatic DDX41 mutations as a secondary hit
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DDX41 expression is haploinsufficient in cases with del(5q) involving DDX41 locus
Summary
Most cases of adult myeloid neoplasms are routinely assumed to be sporadic. Here, we describe an adult familial acute myeloid leukemia (AML) syndrome caused by germline mutations in the DEAD/H-box helicase gene DDX41. DDX41 was also found to be affected by somatic mutations in sporadic cases of myeloid neoplasms as well as in a biallelic fashion in 50% of patients with germline DDX41 mutations. Moreover, corresponding deletions on 5q35.3 present in 6% of cases led to haploinsufficient DDX41 expression. DDX41 lesions caused altered pre-mRNA splicing and RNA processing. DDX41 is exemplary of other RNA helicase genes also affected by somatic mutations, suggesting that they constitute a family of tumor suppressor genes.