Myeloid neoplasms with germline DDX41 mutation

Abstract

to DDX41 mutation and highlights how each of these suggest potential therapeutic opportunities through the use of pathway-specific inhibitors.Keywords DDX41 · Myeloid malignancy · Myelodysplastic syndrome · Acute myeloid leukemia · Germline mutation · Predisposition Familial predisposition to myeloid neoplasmsMyeloid neoplasms are a heterogeneous group of diseases encompassing myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), all of which are characterized by abnormal growth and development of cells of the myeloid blood lineage. These disease groups can be further sub-categorized by a number of different morphological and molecular approaches which may correlate with responses to specific treatments [1]. AML and MDS Abstract Recently, DDX41 mutations have been identified both as germline and acquired somatic mutations in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia. The majority of germline mutations are frameshift mutations suggesting loss of function with DDX41 acting as a tumor suppressor, and there is a common somatic missense mutation found in a majority of germline mutated tumors. Clinically, DDX41 mutations lead to development of high-risk MDS at an age similar to that observed in sporadic cohorts, presenting a unique challenge to hematologists in recognizing the familial context. Functionally, DDX41 has been shown to contribute to multiple pathways and processes including mRNA splicing, innate immunity and rRNA processing. Mutations in DDX41 result in aberrations to each of these in ways that could potentially impact on tumorigenesis-initiation, maintenance or progression. This review discusses the various molecular, clinical and biological aspects of myeloid malignancy predisposition due

Prognostic tumor sequencing panels frequently identify germ line variants associated with hereditary hematopoietic malignancies

“…Two individuals with germ line DDX41 variants acquired second-hit DDX41 mutations (p.Glu345Asp or p.Arg525His). 9 Two pathogenic germ line GATA2 variants were identified ( Table 1). The first was a heterozygous exon 4 deletion in a 23-year-old woman with MDS with monosomy 7.…”

Diverse Roles of DEAD/DEAH-Box Helicases in Innate Immunity and Diseases

“…Mutations in DDX41 have been reported to be associated with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) [125,126]. A number of these mutations, namely p.M155I, p.R164W, p.F183I, p.A225D, p.E247K, p.P321L, and p.I396T, are located in the DEAD domain of DDX41 [123].…”

Familial predisposition of myeloid malignancies: biological and clinical significance of recurrent germ line mutations

“…Therefore, further basic experiments and analysis of a large cohort of affected families are clearly warranted to understand the roles of the mutation and to the establish treatment strategies. Dr. Cheah comprehensively reviews a recent understanding of DDX41 in this issue [10].…”