Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia

Kadono, Moe; Kanai, Akinori; Nagamachi, Akiko; Shinriki, Satoru; Kawata, Jin; Iwato, Koji; Kyo, Taiichi; Oshima, Kiyohiro; Yokoyama, Akihiko; Kawamura, Takeshi; Nagase, Reina; Inoue, Daichi; Kitamura, Toshio; Inaba, Toshiya; Ichinohe, Tatsuo; Matsui, Hirotaka

doi:10.1016/j.exphem.2016.04.017

Cited by 51 publications

(60 citation statements)

References 28 publications

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“…Germline mutations in DDX41 are also able to alter protein isoform usage of DDX41, as the germline mutation M1I [20] leads to a reduction in the full length 70 kDa isoform (p70) and a concomitant increased expression of a 55 kDa isoform (p55) initiating at M127 (our unpublished data and [36]) (Fig. 1).…”

Section: Ddx41 Protein Structurementioning

confidence: 79%

“…Gene set enrichment analysis on DDX41 R525H-positive patient samples and R525H retroviral transduced cord blood implicated perturbation to ribosome biogenesis and pre-rRNA processing. Levels of pre-rRNAs 47S, 41S and 30S were increased and 21S decreased with increases of pre-rRNAs containing the 5′ external transcribed spacer (5′ETS) or internal transcribed spacer 2 (ITS2) compared to ITS1 containing prerRNAs [36] (Fig. 2c).…”

Section: Ddx41 In Post-transcriptional Regulation Of Translation and mentioning

confidence: 98%

“…2c). Overexpression of the DDX41 R525H mutant led to decreased HSC (CD34 + ) growth in culture compared to WT, suggesting a possible mechanism for cytopenias seen in 3 patients with AML with this mutation [36]. Hypocellular bone marrow, consistent with perturbed HSC growth, is common in DDX41 mutant malignancies [19,20].…”

Section: Ddx41 In Post-transcriptional Regulation Of Translation and mentioning

confidence: 99%

“…It is quite common for somatic DDX41 mutations to be seen at low variant allele frequencies (VAF) (e.g., 5-25%) in MDS and AML, which may be missed using some screening technologies. Kadono et al showed in one patient with AML that the VAF for acquired R525H was approaching 50% in CD34 + hematopoietic stem cells (HSC), but was not seen in CD3 + T lymphocytes [36] which can constitute 40-50% peripheral leukocytes. They demonstrated growth inhibition of HSC over-expressing R525H and implied that this mutation predominantly affects myeloid differentiation.…”

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

confidence: 99%

“…1). This shorter p55 isoform lacks the N-terminal nuclear localization signal (NLS) and is localized predominantly in the cytoplasm, unlike p70 which is mainly nuclear [20,36]. Additionally, isoform p55 lacks both sites of TRIM21 ubiquitination and may be expected to have a longer half-life than the full-length protein.…”

Section: Ddx41 Protein Structurementioning

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: Ddx41 Protein Structurementioning

confidence: 79%

Section: Ddx41 In Post-transcriptional Regulation Of Translation and mentioning

confidence: 98%

Section: Ddx41 In Post-transcriptional Regulation Of Translation and mentioning

confidence: 99%

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

confidence: 99%

Section: Ddx41 Protein Structurementioning

confidence: 99%

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Myeloid neoplasms with germline DDX41 mutation

et al. 2017

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Clinical and mechanistic insights into the roles of DDX41 in haematological malignancies

Weinreb

Bowman

2022

FEBS Letters

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DEAD-box Helicase 41 (DDX41) is a member of the DExD/H-box helicase family that has a variety of cellular functions. Of note, germline and somatic mutations in the DDX41 gene are prevalently found in myeloid malignancies. Here, we present a comprehensive and analytic review covering relevant clinical, translational and basic science findings on DDX41. We first describe the initial characterisation of DDX41 mutations in patients affected by myelodysplastic syndromes, their associated clinical characteristics, and current treatment modalities. We then cover the known cellular functions of DDX41, spanning from its discovery in Drosophila as a neuroregulator through its more recently described roles in inflammatory signalling, R-loop metabolism and snoRNA processing. We end with a summary of the identified basic functions of DDX41 that when perturbed may contribute to the underlying pathology of haematologic neoplasms.

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Germline DDX41 mutant predisposition syndromes: Slow driver states to hematological malignancies

Chlon,

Patnaik

2023

American J Hematol

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Germline variants in DDX41 cause inherited predisposition to myeloid malignancies, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Discovered for the first time 8 years ago in a family where an AML patient's brother, father, and paternal grandmother all were affected by AML, DDX41 variants are now appreciated as the most common cause of germline predisposition to adult myeloid malignancies. 1 Inclusion of DDX41 on myeloid sequencing panels now enables characterization of large cohorts of patients bearing these variants.

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Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia

Cited by 51 publications

References 28 publications

Myeloid neoplasms with germline DDX41 mutation

Myeloid neoplasms with germline DDX41 mutation

Clinical and mechanistic insights into the roles of DDX41 in haematological malignancies

Germline DDX41 mutant predisposition syndromes: Slow driver states to hematological malignancies

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