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

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2011-11, Vol.13 (11), p.1035-IN25
• Main Authors: Kao, Hsiao-Wen, Sanada, Masashi, Liang, Der-Cherng, Lai, Chang-Liang, Lee, En-Hui, Kuo, Ming-Chung, Lin, Tung-Liang, Shih, Yu-Shu, Wu, Jin-Hou, Huang, Chein-Fuang, Ogawa, Seishi, Shih, Lee-Yung
• Format: Article
• Language: English
• Subjects: Adult; Aged; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Clone Cells - metabolism; Clone Cells - pathology; Clone Cells - physiology; Cohort Studies; Disease Progression; Female; Gene Frequency; Humans; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Male; Middle Aged; Mutation; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - pathology; Oncology; Proto-Oncogene Proteins c-cbl - genetics; Risk; Young Adult
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1593/neo.111192

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 JAK2V617F , 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.