title: Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome.
abstract: Leukemic transformation (LT) of myeloproliferative neoplasms (MPNs) is associated with a poor prognosis and resistance to therapy. Although previous candidate genetic studies have identified mutations in MPN patients who develop acute leukemia, the complement of genetic abnormalities in MPN patients who undergo LT is not known nor have specific molecular abnormalities been shown to have clinical relevance in this setting. We performed high-throughput resequencing of 22 genes in 53 patients with LT after MPN to characterize the frequency of known myeloid mutations in this entity. In addition to JAK2 and TET2 mutations, which occur commonly in LT after MPN, we identified recurrent mutations in the serine/arginine-rich splicing factor 2 (SRSF2) gene (18.9%) in acute myeloid leukemia (AML) transformed from MPNs. SRSF2 mutations are more common in AML derived from MPNs compared with LT after myelodysplasia (4.8%) or de novo AML (5.6%), respectively (P=.05). Importantly, SRSF2 mutations are associated with worsened overall survival in MPN patients who undergo LT in univariate (P=.03; HR, 2.77; 95% CI, 1.10-7.00) and multivariate analysis (P<.05; HR, 2.11; 95% CI, 1.01-4.42). These data suggest that SRSF2 mutations contribute to the pathogenesis of LT and may guide novel therapeutic approaches for MPN patients who undergo LT.
authors.affiliation: Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Su-Jiang
authors.initials: SJ
authors.lastname: Zhang
authors.forename: Raajit
authors.initials: R
authors.lastname: Rampal
authors.forename: Taghi
authors.initials: T
authors.lastname: Manshouri
authors.forename: Jay
authors.initials: J
authors.lastname: Patel
authors.forename: Nana
authors.initials: N
authors.lastname: Mensah
authors.forename: Andrew
authors.initials: A
authors.lastname: Kayserian
authors.forename: Todd
authors.initials: T
authors.lastname: Hricik
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Cyrus
authors.initials: C
authors.lastname: Hedvat
authors.forename: Mithat
authors.initials: M
authors.lastname: Gönen
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
mesh_terms: D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005787:Gene Frequency; D019337:Hematologic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007938:Leukemia / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D009154:Mutation / Q000502:physiology; D009196:Myeloproliferative Disorders / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D012261:Ribonucleoproteins / Q000235:genetics*; D000068103:Serine-Arginine Splicing Factors; D017381:Spliceosomes / Q000235:genetics / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D012261:Ribonucleoproteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors