ABSTRACT
Chronic myelomonocytic leukaemia (CMML) is a haematological disease currently classified in the category of myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) because of its dual clinical and biological presentation. The molecular biology of CMML is poorly characterized. We studied a series of 53 CMML samples including 31 cases of myeloproliferative form (MP-CMML) and 22 cases of myelodysplastic forms (MD-CMML) using array-comparative genomic hybridisation (aCGH) and sequencing of 13 candidate genes including ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, PTPN11, RUNX1, TET2 and WT1. Mutations in ASXL1 and in the genes associated with proliferation (CBL, FLT3, PTPN11, NRAS) were mainly found in MP-CMML cases. Mutations of ASXL1 correlated with an evolution toward an acutely transformed state: all CMMLs that progressed to acute phase were mutated and none of the unmutated patients had evolved to acute leukaemia. The overall survival of ASXL1 mutated patients was lower than that of unmutated patients.
Subject(s)
Leukemia, Myelomonocytic, Chronic/genetics , Mutation , Repressor Proteins/genetics , Adult , Aged , Aged, 80 and over , Comparative Genomic Hybridization , DNA Mutational Analysis/methods , DNA, Neoplasm/genetics , Disease Progression , Female , Follow-Up Studies , Genes, Neoplasm , Genetic Association Studies , Humans , Male , Middle Aged , Neoplasm Proteins/genetics , Nucleophosmin , Prognosis , Survival AnalysisABSTRACT
BACKGROUND: Gene mutation is an important mechanism of myeloid leukemogenesis. However, the number and combination of gene mutated in myeloid malignancies is still a matter of investigation. METHODS: We searched for mutations in the ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in 65 myelodysplastic syndromes (MDSs) and 64 acute myeloid leukemias (AMLs) without balanced translocation or complex karyotype. RESULTS: Mutations in ASXL1 and CBL were frequent in refractory anemia with excess of blasts. Mutations in TET2 occurred with similar frequency in MDSs and AMLs and associated equally with either ASXL1 or NPM1 mutations. Mutations of RUNX1 were mutually exclusive with TET2 and combined with ASXL1 but not with NPM1. Mutations in FLT3 (mutation and internal tandem duplication), IDH1, IDH2, NPM1 and WT1 occurred primarily in AMLs. CONCLUSION: Only 14% MDSs but half AMLs had at least two mutations in the genes studied. Based on the observed combinations and exclusions we classified the 12 genes into four classes and propose a highly speculative model that at least a mutation in one of each class is necessary for developing AML with simple or normal karyotype.
Subject(s)
Leukemia, Myeloid, Acute/genetics , Mutation/genetics , Myelodysplastic Syndromes/genetics , Neoplasm Proteins/genetics , Aged , Aged, 80 and over , Core Binding Factor Alpha 2 Subunit/genetics , DNA, Neoplasm/genetics , DNA-Binding Proteins/genetics , Dioxygenases , Female , Genes, ras/physiology , Humans , Isocitrate Dehydrogenase/genetics , Janus Kinase 2/genetics , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Myelodysplastic Syndromes/pathology , Nuclear Proteins/genetics , Nucleophosmin , Polymerase Chain Reaction , Prognosis , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-cbl/genetics , Proto-Oncogene Proteins p21(ras) , Repressor Proteins/genetics , WT1 Proteins/genetics , fms-Like Tyrosine Kinase 3/genetics , ras Proteins/geneticsABSTRACT
Chronic myeloproliferative disorders (MPDs) are divided into Philadelphia-positive chronic myeloid leukemia (CML) and Philadelphia-negative disorders including polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis (IMF). Concomitance of a CML and another MPD is a rare event. We report here the case of a patient presenting initially with IMF who developed a Philadelphia-positive CML 7 years later. At the time of CML diagnosis, two distinct clones were present, one with a 13q deletion and one with a t(9;22). We raise the problem of a CML developing on an initial IMF, or two MPDs occurring from a common or two different stem cells.
