Heterogeneous patterns of CEBPalpha mutation status in the progression of myelodysplastic syndrome and chronic myelomonocytic leukemia to acute myelogenous leukemia.
OBJECTIVE
We aimed to assess the role of CEBPalpha mutations in the progression of myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML) and their cooperating mutations.


METHODS
Mutational analysis of CEBPalpha with direct sequencing for each PCR product was done on matched bone marrow samples obtained from 50 adult patients with MDS at diagnosis and at AML transformation. Cloning analysis was used to determine the allelic distribution.


RESULTS
CEBPalpha mutations were identified in four patients at diagnosis of MDS, including one with refractory anemia with excess blasts and three with chronic myelomonocytic leukemia. At AML transformation, three patients retained the identical mutant clones as their initial diagnosis, three acquired the mutations, and one lost CEBPalpha mutation when she gained FLT3/ITD mutation. Together, seven patients had CEBPalpha mutations throughout the disease course; four patients had NH(2)-terminal mutations resulting in a frameshift and truncation of the protein, three of them had two different mutations either on the same alleles or on different alleles, two had missense mutations, and one had a deletion in the basic region leucine zipper domain. Except for one with coexistence of N-ras mutation, no sample harbored cooperating mutations with FLT3 or N-ras genes. CEBPalpha mutations had no influence on the time to AML progression or overall survival.


CONCLUSIONS
Our results show that CEBPalpha mutations play a role in a subset of patients with MDS, especially in chronic myelomonocytic leukemia. The mutation status was heterogeneous, exhibiting identical clone, clonal change, or clonal evolution during the progression to AML.
Shih
Lee-Yung
LY
Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, 199 Tung Hwa North Road, Taipei 105, Taiwan. sly7012@adm.cgmh.org.tw
Huang
Chein-Fuang
CF
Lin
Tung-Liang
TL
Wu
Jin-Hou
JH
Wang
Po-Nan
PN
Dunn
Po
P
Kuo
Ming-Chung
MC
Tang
Tzung-Chih
TC
D000328:Adult; D000368:Aged; D000483:Alleles; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics*; D002471:Cell Transformation, Neoplastic; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D006801:Humans; D016350:Leucine Zippers; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology*; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology*
D022763:CCAAT-Enhancer-Binding Protein-alpha