DDX41-associated susceptibility to myeloid neoplasms

Abstract

Deleterious germ line DDX41 variants confer risk for myeloid neoplasms (MNs) and less frequently for lymphoid malignancies, with autosomal dominant inheritance and an estimated prevalence of 3% among MNs. Germ line 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 germ line genetic testing because >95% of such alleles are germ line. Somatic mutation of the wild-type DDX41 allele occurs in about half of MNs with germ line DDX41 alleles, typically in exons encoding the helicase domain and most frequently as R525H. Several aspects of deleterious germ line DDX41 alleles are noteworthy: (1) certain variants are common in particular populations, (2) MNs develop at older ages typical of de novo disease, challenging the paradigm that inherited cancer risk always causes disease in young people, (3) 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 (4) individuals with deleterious germ line DDX41 variants develop acute severe graft-versus-host disease after allogeneic hematopoietic cell transplantation with wild-type donors more than others unless they receive posttransplant cyclophosphamide, suggesting a proinflammatory 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 messenger RNA splicing, ribosomal RNAs or small nucleolar RNAs processing, and modulation of innate immunity, disruption of which could promote inflammation and drive tumorigenesis.

Graphical abstract

Figure 1.

Deleterious DDX41 germ line variants that confer risk to MNs. The DDX41 protein schematic is shown, including the DEAD-box (green) and helicase (pink) domains. Truncating variants are shown in red, and missense variants in blue.

Figure 2.

Ethnic diversity of deleterious germ line DDX41 alleles. A world map is displayed with common deleterious germ line DDX41 alleles present within particular geographic areas. Standard variant nomenclature is used. Deleterious germ line variants identified within HMs are shown in blue type, and those identified from public databases are given in olive type.

Figure 3.

Master of many: cellular functions of DDX41. DDX41 localizes to both cytoplasmic and nuclear compartments and plays distinct roles in each location. In the nucleus, DDX41 functions in at least 3 processes. Via its association with the catalytically active spliceosome, DDX41 regulates pre-mRNA splicing. Here, it also modulates snoRNA processing, potentially via promoting excision of snoRNA-containing introns found in ribosomal protein genes. DDX41 can also modify pre-rRNA processing, either indirectly via its control of snoRNA processing or perhaps directly via an unknown mechanism. In the nucleus, DDX41 also interacts with R-loops, which comprise RNA:DNA hybrids and ssDNAs. DDX41 insufficiency leads to R-loop accumulation and subsequent increased dsDNA breaks that trigger a cGAS-STING–mediated type I IFN response. Cytoplasmically localized DDX41 can bind to infection-derived or damaged endogenous dsDNA and then promote STING activation and type I IFN response. In addition, DDX41 can modulate cGAS activity via its dsDNA unwinding capabilities by altering the relative amounts of dsDNA-to-ssDNA. For example, the R525H DDX41 mutant, which has intact dsDNA binding activity but diminished unwinding activity, can overstimulate cGAS leading to a heightened type I IFN response. Created with BioRender.com. DDX41, DEAD-box helicase 41; ssDNA, single-stranded DNA.