High Frequency of AML1 Mutations in Patients with Chronic Myelomonocytic Leukemia.

Transcription factor AML1 is essential for normal hematopoiesis. AML1 mutations have been described in myelodysplastic syndrome (MDS), especially in therapy-related MDS but were rarely examined in patients with chronic myelomonocytic leukemia (CMML). We sought to determine the frequency of AML1 mutations in CMML and to assess their role in the progression of CMML to AML. Mutation analysis of AML1 was performed on bone marrow samples from 63 patients with CMML by direct sequencing of all RT-PCR products amplified with 3 overlapping primer pairs which cover the coding sequences of AML1 gene from exon 3 through exon 8. AML1 mutations were detected in 24 of 63 patients (38%) at initial diagnosis, 16 patients had mutations located in Runt homology domain (RHD) (exons 3–5), and 8 had mutations located in the C-terminal region (exons 6–8). One patient had 2 missense mutations in RHD and another one had 2 frameshift mutations in RHD. Taken together, the patterns of 26 mutations consisted of 7 missense mutations, 5 nonsense mutations, 2 silent mutations and 12 frameshift mutations. Ten of 24 patients (41.7%) with mutations progressed to AML compared to 13 of 39 patients (33.3%) without mutations, no difference was observed in the risk of AML transformation between the two groups (P=0.593). Of the 23 patients who progressed to AML, 17 also had bone marrow samples available at AML transformation for mutation analysis. AML1 mutations were detected in 8 of 17 patients at both diagnosis of CMML and AML transformation, all exhibited identical patterns at both phases, with no loss or gain of mutations during AML progression. There were no differences in age, sex, blood counts, percentage of blasts in bone marrow or peripheral blood, subtype of CMML (1 or 2), and cytogenetic risk group between patients with AML1 mutations and those without mutations. Time to AML transformation and overall survival of patients with AML1 mutations did not differ from those without AML1 mutations. Our study showed that AML1 mutations were frequently detected in CMML, with 70% located in RHD. All mutant clones remained identical at initial diagnosis and AML transformation, suggesting that AML1 mutations play an important role in the leukemogenesis in this subset of patients with CMML.