Cargando…
PRPF8 Defects Cause Missplicing in Myeloid Malignancies
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. 50% of PRPF8...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214909/ https://www.ncbi.nlm.nih.gov/pubmed/24781015 http://dx.doi.org/10.1038/leu.2014.144 |
_version_ | 1782342025887088640 |
---|---|
author | Kurtovic-Kozaric, Amina Przychodzen, Bartlomiej Singh, Jarnail Konarska, Maria M. Clemente, Michael J. Otrock, Zaher K. Nakashima, Meghan Hsi, Eric D. Yoshida, Kenichi Ogawa, Seishi Boultwood, Jacqueline Maciejewski, Jaroslaw P. Padgett, Richard A. Makishima, Hideki |
author_facet | Kurtovic-Kozaric, Amina Przychodzen, Bartlomiej Singh, Jarnail Konarska, Maria M. Clemente, Michael J. Otrock, Zaher K. Nakashima, Meghan Hsi, Eric D. Yoshida, Kenichi Ogawa, Seishi Boultwood, Jacqueline Maciejewski, Jaroslaw P. Padgett, Richard A. Makishima, Hideki |
author_sort | Kurtovic-Kozaric, Amina |
collection | PubMed |
description | 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. 50% 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. |
format | Online Article Text |
id | pubmed-4214909 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
spelling | pubmed-42149092015-07-01 PRPF8 Defects Cause Missplicing in Myeloid Malignancies Kurtovic-Kozaric, Amina Przychodzen, Bartlomiej Singh, Jarnail Konarska, Maria M. Clemente, Michael J. Otrock, Zaher K. Nakashima, Meghan Hsi, Eric D. Yoshida, Kenichi Ogawa, Seishi Boultwood, Jacqueline Maciejewski, Jaroslaw P. Padgett, Richard A. Makishima, Hideki Leukemia Article 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. 50% 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. 2014-04-30 2015-01 /pmc/articles/PMC4214909/ /pubmed/24781015 http://dx.doi.org/10.1038/leu.2014.144 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Kurtovic-Kozaric, Amina Przychodzen, Bartlomiej Singh, Jarnail Konarska, Maria M. Clemente, Michael J. Otrock, Zaher K. Nakashima, Meghan Hsi, Eric D. Yoshida, Kenichi Ogawa, Seishi Boultwood, Jacqueline Maciejewski, Jaroslaw P. Padgett, Richard A. Makishima, Hideki PRPF8 Defects Cause Missplicing in Myeloid Malignancies |
title | PRPF8 Defects Cause Missplicing in Myeloid Malignancies |
title_full | PRPF8 Defects Cause Missplicing in Myeloid Malignancies |
title_fullStr | PRPF8 Defects Cause Missplicing in Myeloid Malignancies |
title_full_unstemmed | PRPF8 Defects Cause Missplicing in Myeloid Malignancies |
title_short | PRPF8 Defects Cause Missplicing in Myeloid Malignancies |
title_sort | prpf8 defects cause missplicing in myeloid malignancies |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214909/ https://www.ncbi.nlm.nih.gov/pubmed/24781015 http://dx.doi.org/10.1038/leu.2014.144 |
work_keys_str_mv | AT kurtovickozaricamina prpf8defectscausemissplicinginmyeloidmalignancies AT przychodzenbartlomiej prpf8defectscausemissplicinginmyeloidmalignancies AT singhjarnail prpf8defectscausemissplicinginmyeloidmalignancies AT konarskamariam prpf8defectscausemissplicinginmyeloidmalignancies AT clementemichaelj prpf8defectscausemissplicinginmyeloidmalignancies AT otrockzaherk prpf8defectscausemissplicinginmyeloidmalignancies AT nakashimameghan prpf8defectscausemissplicinginmyeloidmalignancies AT hsiericd prpf8defectscausemissplicinginmyeloidmalignancies AT yoshidakenichi prpf8defectscausemissplicinginmyeloidmalignancies AT ogawaseishi prpf8defectscausemissplicinginmyeloidmalignancies AT boultwoodjacqueline prpf8defectscausemissplicinginmyeloidmalignancies AT maciejewskijaroslawp prpf8defectscausemissplicinginmyeloidmalignancies AT padgettricharda prpf8defectscausemissplicinginmyeloidmalignancies AT makishimahideki prpf8defectscausemissplicinginmyeloidmalignancies |