title: A high occurrence of acquisition and/or expansion of C-CBL mutant clones in the progression of high-risk myelodysplastic syndrome to acute myeloid leukemia.
abstract: The molecular pathogenesis of myelodysplastic syndrome (MDS) and its progression to secondary acute myeloid leukemia (sAML) remain to be explored. Somatic C-CBL mutations were recently described in MDS. Our study aimed to determine the role of C-CBL mutations in the progression of MDS to sAML and sought to correlate with clinicohematological features and outcome. Bone marrow samples from 51 patients with high-risk MDS (13 with refractory cytopenia with multilineage dysplasia, 19 with refractory anemia with excess blast 1, and 19 with refractory anemia with excess blast 2) were analyzed for C-CBL mutations at both diagnosis and sAML in the same individuals. Mutational analysis was performed for exons 7 to 9 of C-CBL gene. Of the 51 paired samples, C-CBL mutations were identified in 6 patients at the sAML phase. One patient retained the identical C-CBL mutation (G415S) at sAML evolution and exhibited clonal expansion. The other five patients acquired C-CBL mutations (Y371S, F418S, L370_Y371 ins L, L399V, and C416W) during sAML evolution. Three of the six patients harboring C-CBL mutations at sAML had additional gene mutations including JAK2(V617F), PTPN11, or N-RAS. There was no significant difference in clinicohematological features and overall survival with respect to C-CBL mutation status. Our results show that C-CBL mutation is very rare (0.6%) in MDS, but acquisition and/or expansion of C-CBL mutant clones occur in 11.8% of patients during sAML transformation. The findings suggest that C-CBL mutations play a role at least in part in a subset of MDS patients during sAML transformation.
authors: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan.
authors: Hsiao-Wen
authors: HW
authors: Kao
authors: Masashi
authors: M
authors: Sanada
authors: Der-Cherng
authors: DC
authors: Liang
authors: Chang-Liang
authors: CL
authors: Lai
authors: En-Hui
authors: EH
authors: Lee
authors: Ming-Chung
authors: MC
authors: Kuo
authors: Tung-Liang
authors: TL
authors: Lin
authors: Yu-Shu
authors: YS
authors: Shih
authors: Jin-Hou
authors: JH
authors: Wu
authors: Chein-Fuang
authors: CF
authors: Huang
authors: Seishi
authors: S
authors: Ogawa
authors: Lee-Yung
authors: LY
authors: Shih
mesh_terms: D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D012306:Risk; D055815:Young Adult
chemical_list: D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human