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. 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.
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH, USA.
A
A
Kurtovic-Kozaric
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH, USA.
B
B
Przychodzen
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
J
J
Singh
Rockefeller University, New York, NY, USA.
M M
MM
Konarska
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH, USA.
M J
MJ
Clemente
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH, USA.
Z K
ZK
Otrock
Department of Pathology, Cleveland Clinic, Cleveland, OH, USA.
M
M
Nakashima
Department of Pathology, Cleveland Clinic, Cleveland, OH, USA.
E D
ED
Hsi
Cancer Genomics Project, Graduate School of Medicine, Tokyo, Japan.
K
K
Yoshida
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Y
Y
Shiraishi
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
K
K
Chiba
Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
H
H
Tanaka
1] Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan [2] Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
S
S
Miyano
1] Cancer Genomics Project, Graduate School of Medicine, Tokyo, Japan [2] Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
S
S
Ogawa
LLR Molecular Haematology Unit, NDCLS, RDM, John Radcliffe Hospital, Oxford, UK.
J
J
Boultwood
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH, USA.
H
H
Makishima
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH, USA.
J P
JP
Maciejewski
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
R A
RA
Padgett
D000595:Amino Acid Sequence; D049109:Cell Proliferation; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008969:Molecular Sequence Data; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
C115374:PRPF8 protein, human; D016601:RNA-Binding Proteins