title: The significance of spliceosome mutations in chronic lymphocytic leukemia.
abstract: Cellular proteins produced via alternative splicing provide neoplastic cells with survival advantage and/or promote neoplastic cell proliferation. Pre-mRNA is spliced by the spliceosome consisting of large complexes of small nuclear RNA (snRNA) and protein subunits. Spliceosome gene mutations were detected in 40-80% of patients with myelodysplastic syndrome (MDS), particularly in those with ringed sideroblasts. Recently, two large whole-genome sequencing studies identified mutations in the spliceosome gene SF3B1 in approximately 10% of patients with chronic lymphocytic leukemia (CLL). Intrigued by these findings, we performed a pathway enrichment analysis and found that, unlike in MDS, in CLL spliceosome mutations exist almost exclusively in SF3B1. Patients with CLL with an SF3B1 gene mutation are characterized by a short progression-free survival and a low 10-year survival rate. Furthermore, the frequency of SF3B1 mutations is significantly higher in chemotherapy treated than in untreated patients with CLL, suggesting that chemotherapy induces SF3B1 gene mutations or selects a population of mutated cells. Whether SF3B1 gene mutations have a role in leukemogenesis, either because of altered splicing or other splicing-unrelated functions such as ectopic expression of Homeobox (Hox) genes previously reported in SF3B1+(/-) mice, remains to be determined.
authors.affiliation: Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Uri
authors.initials: U
authors.lastname: Rozovski
authors.forename: Michael
authors.initials: M
authors.lastname: Keating
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
mesh_terms: D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D017381:Spliceosomes / Q000235:genetics* / Q000378:metabolism