Re-emergence of acute myeloid leukemia in donor cells following allogeneic transplantation in a family with a germline DDX41 mutation

Berger, Gerbrig; Berg, Eva van den; Sikkema‐Raddatz, Birgit; Abbott, Kristin M.; Sinke, Richard J.; Bungener, Laura; Mulder, André B.; Vellenga, Edo

doi:10.1038/leu.2016.310

Cited by 81 publications

(58 citation statements)

References 15 publications

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“…Defection of DDX41 sizably impair pre-mRNA splicing on the evidence of more avid exon skipping and more exon retention in 61 and 95 genes, respectively, observed in mutant cases than controls (87). Recently, resurgence of AML in donor cells in a patient after allogeneic BMT in a family with a germline DDX41 mutation (88). Taken together, these studies strongly support DDX41 as a tumor suppressor gene and defective DDX41 contributes to AML development.…”

Section: Abnormally Spliced (As) Mrnas In Amlmentioning

confidence: 54%

Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

Zhou

Chng

2017

Stem Cell Investig.

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The spliceosome, the cellular splicing machinery, regulates RNA splicing of messenger RNA precursors (pre-mRNAs) into maturation of protein coding RNAs. Recurrent mutations and copy number changes in genes encoding spliceosomal proteins and splicing regulatory factors have tumor promoting or suppressive functions in hematological malignancies, as well as some other cancers. Leukemia stem cell (LSC) populations, although rare, are essential contributors of treatment failure and relapse. Recent researches have provided the compelling evidence that link the erratic spicing activity to the LSC phenotype in acute myeloid leukemia (AML). In this article, we describe the diverse roles of aberrant splicing in hematological malignancies, particularly in AML and their contributions to the characteristics of LSC. We review these promising strategies to exploit the addiction of aberrant spliceosomal machinery for anti-leukemic therapy with aim to eradicate LSC. However, given the complexity and plasticity of spliceosome and not fully known functions of splicing in cancer, the challenges facing the development of the therapeutic strategies targeting RAN splicing are highlighted and future directions are discussed too.

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Section: Abnormally Spliced (As) Mrnas In Amlmentioning

confidence: 54%

Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

Zhou

Chng

2017

Stem Cell Investig.

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“…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: 87%

“…Two recent studies in the literature document the outcomes of using germline DDX41 mutated donor cells for transplantation. The first described a 62-year-old asymptomatic male sibling who was used as an SCT donor for his 58-year brother diagnosed with AML, who subsequently relapsed with donor cell leukemia (DCL) 4 years post-transplant [24]. Molecular analysis identified a previously described germline M1I missense mutation in both brothers.…”

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

confidence: 99%

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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“…In the third scenario, the donor has a genetic predisposing factor, such as CEBPA or DDX41 germline mutations, and transplanted cells acquire the secondary somatic genetic hit and develop DCL (Fig. C) . In the present case, no germline mutations suggestive of a predisposition to leukemia were detected in both the donor and recipient.…”

Section: Discussionmentioning

confidence: 53%

“…Although several genetic mechanisms associated with the molecular pathogenesis of DCL have been discovered, to the best of our knowledge no studies on a large number of patients have been performed. In previous studies, several genetic mechanisms related to the donor were reported, such as occult leukemic/preleukemic subclones in the donor graft and a germline predisposition to leukemia . However, there may be undiscovered mechanisms regarding the molecular pathogenesis or druggable mutations in DCL.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive genetic analysis of donor cell derived leukemia with KMT2A rearrangement

Taniguchi

Muramatsu

Suzuki

et al. 2017

Pediatric Blood & Cancer

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Re-emergence of acute myeloid leukemia in donor cells following allogeneic transplantation in a family with a germline DDX41 mutation

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Cited by 81 publications

References 15 publications

Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

Myeloid neoplasms with germline DDX41 mutation

Comprehensive genetic analysis of donor cell derived leukemia with KMT2A rearrangement

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