DDX41-associated susceptibility to myeloid neoplasms.

Deleterious germline DDX41 variants confer risk for myeloid neoplasms (MNs), and less frequently to lymphoid malignancies, with autosomal dominant inheritance and an estimated prevalence of 3% among MNs. Germline DDX41 variants include truncating alleles that comprise about two thirds of all alleles; missense variants located preferentially within the DEAD box domain; and deletion variants. The identification of a truncating allele on tumor-based molecular profiling should prompt germline genetic testing, since virtually all such alleles are germline. Somatic mutation of the wild-type DDX41 allele occurs in about half of MNs with germline DDX41 alleles, typically in exons encoding the helicase domain and most frequently as R525H. Several aspects of deleterious germline DDX41 alleles are noteworthy: (i) Certain variants are common in particular populations; (ii) MNs develop at older ages typical of de novo disease, challenging the paradigm that inherited cancer risk always causes disease in young people; (iii) Despite equal frequencies of these variants in men and women, men progress to MNs more frequently, suggesting a gender-specific effect on myeloid leukemogenesis; and (iv) Individuals with deleterious germline DDX41 variants develop acute severe graft versus host disease after allogeneic hematopoietic cell transplantation with wild-type donors more than others unless they receive post-transplant cyclophosphamide, suggesting a pro-inflammatory milieu that stimulates donor-derived T-cells. Biochemical studies and animal models have identified DDX41's ability to interact with double stranded DNA and RNA:DNA hybrids with roles in mRNA splicing, rRNAs/snoRNAs processing, and modulation of innate immunity, disruption of which could promote inflammation and drive tumorigenesis.