Donor cell leukemia arising from preleukemic clones with a novel germline DDX41 mutation after allogenic hematopoietic stem cell transplantation

Kobayashi, Shinichi; Kobayashi, Ayako; Osawa, Yukiko; Nagao, Shigeki; Takano, Kosuke; Okada, Yosuke; Tachi, Noriaki; Teramoto, Masaaki; Kawamura, Toshikuni; Horiuchi, Toshikatsu; Kato, Shingo; Maekawa, Taira; Yamamura, Takeshi; Watanabe, Junichi; Harada, Yuka; Harada, Hironori; Sato, Ken; Kimura, Fumihiko

doi:10.1038/leu.2017.44

Cited by 84 publications

(66 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DDX41 is a regulator of mRNA splicing, an activator of interferon response pathways, and a regulator of protein translation (post‐transcriptionally) including p21 . The exact mechanism regarding predisposition to myeloid neoplasms is not known, but coexistence with somatic mutations in a number of genes, including DNMT3A, LUC7L2, RUNX1 , and TP53 have been reported . A connection has previously been reported between DDX41 and myeloid dendritic cells, in which the DEAD‐box domain of DDX41 binds DNA and STING, causing activation of mitogen‐activated protein kinase TBK1, transcription factors and interferon production …”

Section: Description Of Phenotypic Traits and Genetic Resultsmentioning

confidence: 99%

Putative new childhood leukemia cancer predisposition syndrome caused by germline bi‐allelic missense mutations in DDX41

Diness

Risom

Frandsen

et al. 2018

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

DDX41 has recently been identified as a new autosomal dominantly inherited cancer predisposition syndrome causing increased risk of adult onset acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We report for the first time compound heterozygote germline missense DDX41 mutations located in the DEAD-box domain, identified in two siblings by exome sequencing. Both siblings have slight dysmorphic findings, psychomotor delays and intellectual disability, and one developed blastic plasmacytoid dendritic cell neoplasm (BPDCN) at age five. RNA-sequencing of bone marrow showed DDX41 expression including both mutations. However, the allele fraction of p.Pro321Leu accounted for 96% in the RNA-sequencing indicating this mutation to be the more significant variant. Exome sequencing of the leukemic blasts identified no additional known driver mutations. There is no pattern indicating autosomal dominantly inherited cancer predisposition in the family, but the father has sarcoidosis, which has been associated with heterozygous DDX41 mutation. We propose that bi-allelic mutations in DDX41 could potentially be a new cancer predisposition syndrome associated with delayed psychomotor development.

show abstract

Section: Description Of Phenotypic Traits and Genetic Resultsmentioning

confidence: 99%

Putative new childhood leukemia cancer predisposition syndrome caused by germline bi‐allelic missense mutations in DDX41

Diness

Risom

Frandsen

et al. 2018

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

show abstract

“…Donor‐derived leukemia has been reported in several DDX41 ‐affected families, occurring after allogeneic SCT from a mutation‐positive, related donor. Notably, these cases of donor‐derived leukemia reportedly occurred without any hematopoietic abnormalities identified in the mutation‐positive donors, indicating that HSC stress during SCT and/or host factors can promote malignant expansion . In our case, the patient's children were evaluated expeditiously for comprehensive genetic counseling and testing, and both children elected to proceed with single‐site germline analysis of c.572‐1G>A on peripheral blood.…”

Section: Identification Of An Inherited Leukemia Predisposition Throumentioning

confidence: 85%

Improving the detection of patients with inherited predispositions to hematologic malignancies using next‐generation sequencing‐based leukemia prognostication panels

DiNardo

Routbort

Bannon

et al. 2018

Cancer

View full text Add to dashboard Cite

Recognizing and referring patients with possible inherited cancer predisposition syndromes for appropriate genetic evaluation and testing provides insights into optimal patient treatment approaches and also can provide education and testing opportunities for family members. Next-generation sequencing (NGS)-based, targeted genotyping for somatic mutations is increasingly used in the diagnosis, prognostication, and treatment selection for patients with hematologic malignancies. However, certain mutations that may be somatically acquired can also be present as germline mutations in some individuals and families. Whether the results of NGS-based leukemia panels can be used to inform decisions and subsequent evaluation of patients with possible inherited cancer predispositions has not been described previously. Because a normal control often is not available when using NGS panels in patients with hematologic malignancies, NGS panel results offer both an opportunity and a challenge to determine the origin and pathogenicity of identified mutations. In the absence of a matched germline control, variant allele frequency (VAF) estimation and data from publically available data sets provide important clues to the possible germline origin of a variant. Careful annotation and review of NGS panels in patients with hematologic malignancies can provide a useful screening tool to systematically improve upon the detection of potentially pathogenic germline variants. Cancer 2018;124:2704-2713. © 2018 American Cancer Society.

show abstract

“…Molecular analysis identified a previously described germline M1I missense mutation in both brothers. Similarly in the second study, a 49-year-old individual who developed MDS received a bone marrow transplant from his unaffected sibling and later relapsed with DCL, where both individuals were found to be carriers of a novel DDX41 A500Cfs*9 mutation (Table 1) [33]. Of note, the donors described in both studies were not reported to have developed HM and this suggests that HSC stress (i.e., reconstitution of recipient hematopoiesis) may be a potential trigger for HM development [34].…”

Section: Acquired Co-operating Mutations and Clonal Evolution In Germmentioning

confidence: 99%

Myeloid neoplasms with germline DDX41 mutation

et al. 2017

View full text Add to dashboard Cite

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

show abstract

Donor cell leukemia arising from preleukemic clones with a novel germline DDX41 mutation after allogenic hematopoietic stem cell transplantation

Cited by 84 publications

References 9 publications

Putative new childhood leukemia cancer predisposition syndrome caused by germline bi‐allelic missense mutations in DDX41

Putative new childhood leukemia cancer predisposition syndrome caused by germline bi‐allelic missense mutations in DDX41

Improving the detection of patients with inherited predispositions to hematologic malignancies using next‐generation sequencing‐based leukemia prognostication panels

Myeloid neoplasms with germline DDX41 mutation

Contact Info

Product

Resources

About