PRPF8 defects cause missplicing in myeloid malignancies

Kurtovic-Kozaric, Amina; Przychodzen, B.; Singh, Jagjit; Konarska, Maria M.; Clemente, Michael J.; Otrock, Zaher K.; Nakashima, Megan O.; Hsi, Eric D.; Yoshida, Kenichi; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Ogawa, Seishi; Boultwood, Jacqueline; Makishima, Hideki; Maciejewski, Jaroslaw P.; Padgett, Richard A.

doi:10.1038/leu.2014.144

Cited by 97 publications

(63 citation statements)

References 51 publications

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“…Notably, 50% of PRPF8 mutant and deletion of chromosome 17p cases were found in AML. Survival analysis confirmed that PRPF8 was associated with poor prognosis (91).…”

Section: Abnormally Spliced (As) Mrnas In Amlmentioning

confidence: 54%

“…Combing these evidences, we could imply that PRPF8 is required for haematopoietic development and defective PRPF8 could be conducive to myeloid malignancies. Indeed, KurtovicKozaric and coworkers identified either recurrent somatic PRPF8 mutations or hemizygous deletions in 3.3% (15 out of 447 cases) and 5.3% (24 out of 450 cases) of myeloid neoplasms, respectively (91). Notably, 50% of PRPF8 mutant and deletion of chromosome 17p cases were found in AML.…”

Section: Abnormally Spliced (As) Mrnas In Amlmentioning

confidence: 99%

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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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“…Notably, 50% of PRPF8 mutant and deletion of chromosome 17p cases were found in AML. Survival analysis confirmed that PRPF8 was associated with poor prognosis (91).…”

Section: Abnormally Spliced (As) Mrnas In Amlmentioning

confidence: 54%

Section: Abnormally Spliced (As) Mrnas In Amlmentioning

confidence: 99%

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

Zhou

Chng

2017

Stem Cell Investig.

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“…1) [4]. Along with these, multiple loss-of-function mutations [5][6][7][8][9][10][11][12], and recurrent activated/gain-of-function mutations [13][14][15][16] are likely to be the promising candidates for future development of novel therapy by inhibitory compounds (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

Somatic SETBP1 mutations in myeloid neoplasms

Makishima

2017

Int J Hematol

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“…Similarly, mutations in PRPF8 have been identified in MDS and AML patients where decreased PRPF8 expression is associated with increased exon skipping [53], possibly due to a splicing proofreading defect [53]. While DDX41 R525H is associated with reduced binding to SF3B1 and PRPF8, DDX41 mutations have not been reported in association with MDS with ring sideroblasts that is often characteristic of mutations in SF3B1 [50] and PRPF8 [53].…”

Section: Ddx41 In Mrna Splicingmentioning

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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PRPF8 defects cause missplicing in myeloid malignancies

Cited by 97 publications

References 51 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

Somatic SETBP1 mutations in myeloid neoplasms

Myeloid neoplasms with germline DDX41 mutation

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