Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms

Polprasert, Chantana; Schulze, Isabell; Sekeres, Mikkael A.; Makishima, Hideki; Przychodzen, Bartlomiej; Hosono, Naoko; Singh, Jarnail; Padgett, Richard A.; Gu, Xiaorong; Phillips, James G.; Clemente, Michael J.; Parker, Yvonne; Lindner, Daniel J.; Dienes, Brittney; Jankowsky, Eckhard; Saunthararajah, Yogen; Du, Yang; Oakley, Karen L.; Nguyen, Nhu; Mukherjee, Sudipto; Pabst, Caroline; Godley, Lucy A.; Churpek, Jane E.; Pollyea, Daniel A.; Krug, Utz; Berdel, Wolfgang E.; Klein, Hans-Ulrich; Dugas, Martin; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Yoshida, Kenichi; Ogawa, Seishi; Müller‐Tidow, Carsten; Maciejewski, Jaroslaw P.

doi:10.1016/j.ccell.2015.03.017

Cited by 379 publications

(473 citation statements)

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“…Of the eight, three harbored the germline D140Gfs*2 variant, confirming its status as the most common site of mutation in Caucasian populations (Fig. 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].…”

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

confidence: 56%

“…In the same study cohort, further screening of both familial and sporadic myeloid malignancies identified a further 10 families or singleton cases carrying the germline D140Gfs*2 mutation, as well as identifying additional germline mutations such as I1396T, F183I, Q52fs and M155I mutations ( Fig. 1) [19]. Somatic DDX41 mutations were frequently observed in myeloid tumors of germline DDX41 mutated individuals.…”

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

confidence: 94%

“…The most common was the DDX41 R525H mutation seen in the index family and confirmed as present in trans, relative to the germline lesion in one case (i.e., biallelic). Other somatic DDX41 mutations including A225D, E247K, P321L and a splice donor site mutation were identified in tumors from other individuals, collectively identifying somatic DDX41 mutations in 50% of tumors from germline DDX41 mutated individuals (see Table 1) [19].…”

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

confidence: 98%

“…It belongs to the DEAD-box helicase family of genes that have been characterized in multiple cellular roles [18]. DDX41 was first identified as a predisposition gene for myeloid malignancy in a family with 4 family members affected by AML or MDS, where a germline frameshift mutation in DDX41 D140Gfs*2 was found to segregate in all tested affected individuals [19]. AML samples from 2 of the affected individuals had acquired an identical R525H mutation also in DDX41.…”

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

confidence: 99%

“…Following the initial description of germline DDX41 mutations [19], we reported an additional eight families Fig. 1 Germline and somatic DDX41 mutations in hematological malignancies.…”

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

confidence: 99%

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Myeloid neoplasms with germline DDX41 mutation

et al. 2017

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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

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

confidence: 56%

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

confidence: 94%

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

confidence: 98%

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

confidence: 99%

“…Following the initial description of germline DDX41 mutations [19], we reported an additional eight families Fig. 1 Germline and somatic DDX41 mutations in hematological malignancies.…”

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

confidence: 99%

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Myeloid neoplasms with germline DDX41 mutation

et al. 2017

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Diagnosis and Treatment of Myelodysplastic Syndromes

Sekeres

Taylor

2022

JAMA

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he myelodysplastic neoplasms (MDS), formerly known as myelodysplastic syndromes, are a group of cancers characterized by failure of bone marrow stem cells to mature into normal-functioning blood cells. MDS are characterized by reduced numbers of peripheral blood cells, an increased risk of acute myeloid leukemia transformation, and reduced survival, with a 5-year survival rate of approximately 37%. 1,2 The yearly incidence of MDS is approximately 4 per 100 000 people. 3 MDS are more common in men (with yearly incidence rates of approxi-mately 5.4 per 100 000 vs 2.9 per 100 000 for women) and are more common among people who are White compared with people who are Asian/Pacific Islander (4.0 per 100 000), Black (2.7 per 100 000), or Hispanic (2.9 per 100 000), and among people who are older. 3 The median age of diagnosis is approximately 70 years, and the yearly incidence rate increases to 25 per 100 000 in people aged 65 years and older. 3 Older age is associated with clonal hematopoiesis of indeterminate potential, which is considered a precursor to MDS. 4 Additional risk factors IMPORTANCE Myelodysplastic neoplasms (MDS), formerly known as myelodysplastic syndromes, are clonal hematopoietic malignancies that cause morphologic bone marrow dysplasia along with anemia, neutropenia, or thrombocytopenia. MDS are associated with an increased risk of acute myeloid leukemia (AML). The yearly incidence of MDS is approximately 4 per 100 000 people in the United States and is higher among patients with advanced age.OBSERVATIONS MDS are characterized by reduced numbers of peripheral blood cells, an increased risk of acute myeloid leukemia transformation, and reduced survival. The median age at diagnosis is approximately 70 years, and the yearly incidence rate increases to 25 per 100 000 in people aged 65 years and older. Risk factors associated with MDS include older age and prior exposures to toxins such as chemotherapy or radiation therapy. MDS are more common in men compared with women (with yearly incidence rates of approximately 5.4 vs 2.9 per 100 000). MDS typically has an insidious presentation, consisting of signs and symptoms associated with anemia, thrombocytopenia, and neutropenia. MDS can be categorized into subtypes that are associated with lower or higher risk for acute myeloid leukemia transformation and that help with therapy selection. Patients with lower-risk MDS have a median survival of approximately 3 to 10 years, whereas patients with higher-risk disease have a median survival of less than 3 years. Therapy for lower-risk MDS is selected based on whether the primary clinical characteristic is anemia, thrombocytopenia, or neutropenia. Management focuses on treating symptoms and reducing the number of required transfusions in patients with low-risk disease. For patients with lower-risk MDS, erythropoiesis stimulating agents, such as recombinant humanized erythropoietin or the longer-acting erythropoietin, darbepoetin alfa, can improve anemia in 15% to 40% of patients for a median of 8 to 23 months. For th...

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Contemporary Management of Acute Myeloid Leukemia

Venugopal,

Sekeres

2024

JAMA Oncol

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ImportanceAcute myeloid leukemia (AML) is a clonal hematopoietic cancer that disrupts normal hematopoiesis, ultimately leading to bone marrow failure and death. The annual incidence rate of AML is 4.1 per 100 000 people in the US and is higher in patients older than 65 years. Acute myeloid leukemia includes numerous subgroups with heterogeneous molecular profiles, treatment response, and prognosis. This review discusses the evidence supporting frontline therapies in AML, the major principles that guide therapy, and progress with molecularly targeted therapy.ObservationsAcute myeloid leukemia is a genetically complex, dynamic disease. The most commonly altered genes include FLT3, NPM1, DNMT3A, IDH1, IDH2, TET2, RUNX1, NRAS, and TP53. The incidence of these alterations varies by patient age, history of antecedent hematologic cancer, and previous exposure to chemotherapy and/or radiotherapy for any cancer. Since 2010, molecular data have been incorporated into AML prognostication, gradually leading to incorporation of targeted therapies into the initial treatment approach of induction chemotherapy and subsequent management. The first molecularly targeted inhibitor, midostaurin, was approved to treat patients with AML with FLT3 variants in 2017. Since then, the understanding of the molecular pathogenesis of AML has expanded, allowing the identification of additional potential targets for drug therapy, treatment incorporation of molecularly targeted therapies (midostaurin, gilteritinib, and quizartinib targeting FLT3 variants; ivosidenib and olutasidenib targeting IDH1 variants, and enasidenib targeting IDH2), and identification of rational combination regimens. The approval of hypomethylating agents combined with venetoclax has revolutionized the therapy of AML in older adults, extending survival over monotherapy. Additionally, patients are now referred for hematopoietic cell transplant on a more rational basis.Conclusions and RelevanceIn the era of genomic medicine, AML treatment is customized to the patient’s comorbidities and AML genomic profile.

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Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms

Cited by 379 publications

References 42 publications

Myeloid neoplasms with germline DDX41 mutation

Myeloid neoplasms with germline DDX41 mutation

Diagnosis and Treatment of Myelodysplastic Syndromes

Contemporary Management of Acute Myeloid Leukemia

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