title: Activating CBL mutations are associated with a distinct MDS/MPN phenotype.
abstract: Activating point mutations in CBL have recently been identified in diverse subtypes of myeloid neoplasms. Because detailed clinical and hematological characteristics of CBL-mutated cases is lacking, we screened 156 BCR-ABL and JAK2 V617F negative patients with myeloproliferative neoplasms (MPN) and overlap syndromes between myelodysplastic syndrome (MDS) and MPN (MPS/MPN) for mutations in exons 8 and 9 of CBL by denaturing high-performance liquid chromatography and direct sequencing. CBL mutations were identified in 16/156 patients (10%), of which five also carried mutations in EZH2 (n = 3) and TET2 (n = 2). Comprehensive clinical and hematological characteristics were available from 13/16 patients (81%). In addition to splenomegaly (77%), striking common hematological features were CML-like left-shifted leukocytosis (85%) with monocytosis (85%), anemia (100%), and thrombocytopenia (62%). Thrombocytosis was not observed in any patient. Relevant bone marrow features (n = 12) included hypercellularity (92%) with marked granulopoiesis (92%), nonclustered microlobulated megakaryocytes (83%), and marrow fibrosis (83%). Nine deaths (progression to secondary acute myeloid leukemia/blast phase, n = 7; cytopenia complications, n = 2) were recorded. Three-year survival rate was 27%, possibly indicating poor prognosis of CBL mutated MDS/MPN patients.
authors.affiliation: III. Medizinische Klinik, Universitätsmedizin Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
authors.forename: Juliana
authors.initials: J
authors.lastname: Schwaab
authors.forename: Thomas
authors.initials: T
authors.lastname: Ernst
authors.forename: Philipp
authors.initials: P
authors.lastname: Erben
authors.forename: Jenny
authors.initials: J
authors.lastname: Rinke
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Philipp
authors.initials: P
authors.lastname: Ströbel
authors.forename: Georgia
authors.initials: G
authors.lastname: Metzgeroth
authors.forename: Max
authors.initials: M
authors.lastname: Mossner
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Reiter
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases; D000071221:Enhancer of Zeste Homolog 2 Protein; D005091:Exons; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D006801:Humans; D007964:Leukocytosis / Q000209:etiology; D008297:Male; D008875:Middle Aged; D054437:Myelodysplastic-Myeloproliferative Diseases / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017354:Point Mutation; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013163:Splenomegaly / Q000209:etiology; D016019:Survival Analysis; D013921:Thrombocytopenia / Q000209:etiology; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C541081:TET2 protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human