Germline heterozygous DDX41 variants in a subset of familial myelodysplasia and acute myeloid leukemia

Cardoso, Shirleny; Ryan, Gavin; Walne, Amanda J.; Ellison, Alicia; Lowe, Robert; Tummala, Hemanth; Río-Machín, Ana; Collopy, Laura C.; Seraihi, Ahad Al; Wallis, Yvonne; Page, Paula; Akiki, Susanna; Fitzgibbon, Jude; Vulliamy, Tom; Dokal, Inderjeet

doi:10.1038/leu.2016.124

Cited by 62 publications

(38 citation statements)

References 13 publications

(18 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1, 14 families) [19][20][21]. Two families carried a novel germline M1I mutation which was also seen in subsequent studies, making it the second most frequent germline DDX41 mutation in Caucasian populations (5 families) [20,[22][23][24]. Interestingly, in one family, a germline variant identical to the commonly acquired R525H mutation was identified (confirmed germline in hair).…”

Section: Mutation Of Ddx41 In Familial Hematological Malignancies (Fhm)mentioning

confidence: 88%

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

Section: Mutation Of Ddx41 In Familial Hematological Malignancies (Fhm)mentioning

confidence: 88%

Myeloid neoplasms with germline DDX41 mutation

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The spliceosomal components frequently affected in MDS include the biochemically welldefined factors SF3B1, SRSF2, and U2AF1 (Yoshida et al 2011;reviewed by Yoshida and Ogawa 2014). More recent studies have implicated DDX41 (Ding et al 2012;Lewinsohn et al 2015;Polprasert et al 2015;Cardoso et al 2016;Li et al 2016;Diness et al 2018;reviewed by Maciejewski et al 2017), a DEAD-box RNA helicase highly conserved in metazoans, whose precise biochemical function in the spliceosome is less well understood. DDX41 appears to be specifically recruited to the catalytically active C complex (Jurica et al 2002;Bessonov et al 2008), which performs the second step of splicing in which the 5' and 3' exons are ligated and an intronic lariat is released.…”

Section: Introductionmentioning

confidence: 99%

“…For example, examination of clonal evolution of relapsed AML cases identified DDX41 as one of several genes found to be mutated in secondary tumors but not the primary tumors, suggesting it plays a role as a tumor suppressor and might be causative for disease progression (Ding et al 2012). By contrast, studies of familial acute myeloid leukemia syndromes suggest that preexisting germline DDX41 mutations in trans to newly arising somatic mutations cause the development of hematological malignancies (Polprasert et al 2015;Cardoso et al 2016;Lewinsohn et al 2016;Li et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Insights into the involvement of spliceosomal mutations in myelodysplastic disorders from an analysis of SACY-1/DDX41 inCaenorhabditis elegans

Greenstein

Tsukamoto

Gearhart

et al. 2019

Preprint

View full text Add to dashboard Cite

Mutations affecting spliceosomal proteins are frequently found in hematological malignancies. DDX41/Abstrakt is a metazoan-specific spliceosomal DEAD-box RNA helicase recurrently mutated in inherited and relapsing myelodysplastic syndromes and acute myeloid leukemia. The genetic properties and genomic impacts of disease-causing mutations in spliceosomal proteins have been uncertain. Here we conduct a comprehensive molecular genetic analysis of the C. elegans DDX41 ortholog, SACY-1. Our results reveal that multiple sacy-1/DDX41 missense mutations, including the R525H human oncogenic variant, exhibit antimorphic activity that likely compromises the function of the spliceosome. The genomic consequences of SACY-1 depletion include splicing-splicingindependent and splicing-dependent alterations in the transcriptome. ABSTRACTMutations affecting spliceosomal proteins are frequently found in hematological malignancies, including myelodysplastic syndromes and acute myeloid leukemia. DDX41/Abstrakt is a metazoanspecific spliceosomal DEAD-box RNA helicase found to be recurrently mutated in inherited myelodysplastic syndromes and in relapsing cases of acute myeloid leukemia. The genetic properties and genomic impacts of disease-causing missense mutations in DDX41 and other spliceosomal proteins have been uncertain. Here we conduct a comprehensive molecular genetic analysis of the C. elegans DDX41 ortholog, SACY-1. Our results reveal general essential functions for SACY-1 in both the germline and the soma, as well as specific functions affecting germline sex determination and cell cycle control. Certain sacy-1/DDX41 mutations, including the R525H human oncogenic variant, confer antimorphic activity, suggesting that they compromise the function of the spliceosome. Consistent with these findings, sacy-1 exhibits synthetic lethal interactions with several spliceosomal components, and biochemical analyses suggest that SACY-1 is a component of the C. elegans spliceosome. We used the auxin-inducible degradation system to analyze the impact of SACY-1 on the transcriptome using RNA sequencing. SACY-1 depletion impacts the transcriptome through splicing-independent and splicingdependent mechanisms. The observed transcriptome changes suggest that disruption of spliceosomal function induces a stress response. Altered 3' splice site usage represents the predominant splicing defect observed upon SACY-1 depletion, consistent with a role for SACY-1 as a second-step splicing factor. Missplicing events appear more prevalent in the soma than the germline, suggesting that surveillance mechanisms protect the germline from aberrant splicing.

show abstract

“…To date, approximately 20 families have been described in the USA, UK, and Australia [8][9][10][11]. Myeloid neoplasms arise due to inherited mutations in the DDX41 gene (DEAD/H-box helicase gene) on chromosome 5q35.3.…”

Section: Myeloid Neoplasms With Germline Ddx41 Mutationmentioning

confidence: 99%

Myeloid Neoplasms with Germline Predisposition

Geyer¹

2018

Pathobiology

View full text Add to dashboard Cite

The updated 2016 WHO classification of hematopoietic tumors has a new category: “myeloid neoplasms with germline predisposition.” These entities are rare, but are also currently underdiagnosed and underreported. Recognition is critical for appropriate clinical evaluation and therapy, with potential implications for the patient’s entire family. The WHO includes 3 categories of myeloid neoplasms with germline predisposition: neoplasms without preexisting conditions, neoplasms with a history of thrombocytopenia, and neoplasms with other organ dysfunction. Specialized molecular testing is frequently necessary to make the diagnosis, as the presence of one of the implicated mutations is not sufficient for diagnosis and should be confirmed with germline DNA evaluation. Many families have unique mutations that are not detected by targeted sequencing panels. Periodic bone marrow (BM) examinations are recommended to assess patients’ baseline morphology and rule out evidence of disease progression. Thus, accurate diagnosis requires a careful recording of clinical history, a BM morphology evaluation, and advanced molecular testing.

show abstract

Germline heterozygous DDX41 variants in a subset of familial myelodysplasia and acute myeloid leukemia

Cited by 62 publications

References 13 publications

Myeloid neoplasms with germline DDX41 mutation

Myeloid neoplasms with germline DDX41 mutation

Insights into the involvement of spliceosomal mutations in myelodysplastic disorders from an analysis of SACY-1/DDX41 inCaenorhabditis elegans

Myeloid Neoplasms with Germline Predisposition

Contact Info

Product

Resources

About