Abstract
Mutations of spliceosome components are common in myeloid neoplasms. One of the affected genes, PRPF8, encodes the most evolutionarily conserved spliceosomal protein. We identified either recurrent somatic PRPF8 mutations or hemizygous deletions in 15/447 and 24/450 cases, respectively. Fifty percent of PRPF8 mutant and del(17p) cases were found in AML and conveyed poor prognosis. PRPF8 defects correlated with increased myeloblasts and ring sideroblasts in cases without SF3B1 mutations. Knockdown of PRPF8 in K562 and CD34+ primary bone marrow cells increased proliferative capacity. Whole-RNA deep sequencing of primary cells from patients with PRPF8 abnormalities demonstrated consistent missplicing defects. In yeast models, homologous mutations introduced into Prp8 abrogated a block experimentally produced in the second step of the RNA splicing process, suggesting that the mutants have defects in proof-reading functions. In sum, the exploration of clinical and functional consequences suggests that PRPF8 is a novel leukemogenic gene in myeloid neoplasms with a distinct phenotype likely manifested through aberrant splicing.
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Acknowledgements
This work was supported by National Institutes of Health grants R01 HL082983 (JPM), RO1 GM093074 (RAP), and RO1 GM049044 (MMK), Scott Hamilton CARES Initiative (HM), Aplastic Anemia & MDS International Foundation (HM), Fulbright Scholar Fellowship, US Department of State (AK). We thank Naoko Hosono, Kathryn Guinta and Brittney Dienes for experimental and technical assistance.
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AK, JPM, RAP, MMK and HM designed research, performed research, collected data, performed statistical analysis and wrote the manuscript; BP and MC designed research, performed statistical analysis, contributed analytical tools, interpreted data and wrote the manuscript. JS, MMK, MN, ZKO, EDH, KY, SO and JB collected and interpreted data.
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Kurtovic-Kozaric, A., Przychodzen, B., Singh, J. et al. PRPF8 defects cause missplicing in myeloid malignancies. Leukemia 29, 126–136 (2015). https://doi.org/10.1038/leu.2014.144
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DOI: https://doi.org/10.1038/leu.2014.144
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