Germline DDX41 mutations define a significant entity within adult MDS/AML patients

Sébert, Marie; Passet, Marie; Raimbault, Anna; Rahmé, Ramy; Raffoux, Emmanuel; Fontbrune, Flore Sicre de; Cerrano, Marco; Quentin, Samuel; Vasquez, Nadia; Costa, Mélanie Da; Boissel, Nicolas; Dombret, Hervé; Latour, Régis Peffault de; Socié, Gérard; Itzykson, Raphaël; Fenaux, Pierre; Soulier, Jean; Adès, Lionel; Clappier, Emmanuelle

doi:10.1182/blood.2019000909

Cited by 171 publications

(193 citation statements)

References 19 publications

(25 reference statements)

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“…While it is possible that the genetic properties of this mutation might differ between C. elegans and mammalian systems, it is worthwhile noting that the oncogenic variant must support the high levels of proliferation characteristic of neoplastic cells. While all the sacy-1 mutations we isolated in forward genetic screens occur at conserved amino acids, none of them match the oncogenic mutations thus far isolated (Polprasert et al 2015;Cardoso et al 2016;Lewinsohn et al 2016;Li et al 2016;Diness et al 2018 ;Sébert et al 2019). This observation is consistent with the idea that the oncogenic mutations are at most weakly antagonizing or weak reduction-of-function mutations, and thus would not have been isolated in forward genetic screens that require a substantial reduction in function.…”

Section: Discussionmentioning

confidence: 91%

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

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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.

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Section: Discussionmentioning

confidence: 91%

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

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“…Patients with myeloid neoplasms with DDX41 mutations were initially reported to have a poor prognosis but this analysis included both germline and somatic mutations, including patients with 5q deletions spanning the DDX41 locus . In contrast, a recent study including only patients with germline mutations showed no significant difference in survival …”

Section: Myeloid Neoplasms With Germline Predisposition Without a Prementioning

confidence: 99%

Genetic predisposition in acute leukaemia

Wiggins

Stevenson

2020

Int J Lab Hematology

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A small but important proportion of patients with myelodysplasia (MDS) and acute leukaemia (AL) have underlying germline mutations in leukaemia susceptibility genes. The majority of these variants predispose to myeloid neoplasms with a smaller number associated with acute lymphoblastic leukaemia (ALL). The 2016 revision of the WHO classification of tumours of haematopoietic and lymphoid tissues has defined a number of myeloid neoplasms with germline predisposition (Blood, 127, 2016, 2391) alerting clinicians to the importance of this underlying diagnosis. Advances in genetic technology and access to testing will undoubtably result in increased numbers of patients and families with leukaemia predisposition syndromes being identified. Here we summarize the salient biology and genetic and clinical features of a number of these conditions including some more recently described genetic variants.

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“…Com mais de 70 famílias já descritas, vem se tornando uma das propensões germinativas mais descritas 31 . Dois grandes estudos em populações não selecionadas de LMA e SMD identificaram presença da mutação, provavelmente, germinativa em quase 2,5% dos casos, fazendo com que esta seja provavelmente a NMPG mais comum 32,33 . Ela difere das demais propensões familiares pelo tempo de latência maior e mediana de idade ao diagnóstico em torno de 70 anos 32,33 .…”

Section: Neoplasia Mieloide Com Mutação Germinativa De Ddx41unclassified

“…Dois grandes estudos em populações não selecionadas de LMA e SMD identificaram presença da mutação, provavelmente, germinativa em quase 2,5% dos casos, fazendo com que esta seja provavelmente a NMPG mais comum 32,33 . Ela difere das demais propensões familiares pelo tempo de latência maior e mediana de idade ao diagnóstico em torno de 70 anos 32,33 . O tipo de mutação pode sugerir a origem germinativa, uma vez que até o momento não foram encontradas mutações do tipo frameshift somaticamente 32,34 .…”

Section: Neoplasia Mieloide Com Mutação Germinativa De Ddx41unclassified

“…A necessidade de mutação do alelo selvagem ou novas mutações somáticas indica que a haploinsuficiência de DDX41 é capaz de manter a hematopoese normal 35 . Do ponto de vista clinico, além da idade mais elevada do que habitualmente encontrada nas predisposições germinativas, há preponderância de acometimento do sexo masculino, aumento da predisposição a SMD de alto risco e LMA com cariótipo normal, medula óssea com marcada diseritropoiética 31,34,35 e, ao contrário do que se acreditava, aproximadamente metade dos pacientes apresenta período de citopenias antes do diagnóstico de neoplasia mieloide 32,33 .…”

Section: Neoplasia Mieloide Com Mutação Germinativa De Ddx41unclassified

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Estudo citogenético e molecular de síndromes mielodisplásicas / leucemia mieloide aguda familiar

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Germline DDX41 mutations define a significant entity within adult MDS/AML patients

Abstract: This report presents the intriguing observation that cases with germline DEAD-box helicase 41 (DDX41) mutations represent a unique entity among adult myeloid neoplasms.

Cited by 171 publications

References 19 publications

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

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

Genetic predisposition in acute leukaemia

Estudo citogenético e molecular de síndromes mielodisplásicas / leucemia mieloide aguda familiar

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