Background: Transcription factor AML1/RUNX1 is essential for normal hematopoiesis. AML1 mutations have been described in radiation-associated and therapy-related myelodysplastic syndrome (MDS) and have rarely been reported in patients with chronic myelomonocytic leukemia (CMML).

Aims: We sought (1) to define the frequencies of AML1 mutations in de novo MDS and CMML, and (2) to compare the difference in mutation patterns between the two disorders.

Methods: AML1 mutations were examined on bone marrow samples obtained at initial diagnosis from 107 patients with de novo MDS (12 RCMD, 45 RAEB1 and 50 RAEB2) and 79 patients with CMML (53 CMML1 and 26 CMML2). Mutational analysis was performed by direct sequencing of all RT-PCR products amplified with 3 overlapping primer pairs which cover the entire coding sequences of AML1b gene from exon 1 through exon 8. Samples with abnormal sequencing results were subjected to repeated PCR and sequencing using genomic DNA with alternative primers.

Results: Seventeen of 107 patients with MDS (15.9%) had 20 AML1 mutations; 8 mutations were located in Runt homology domain (RHD) (exons 3–5) and 12 mutations were located in the non-RHD region (exons 6–8). The 20 AML1 mutations included 9 missense mutations, 5 nonsense mutations, 2 frameshift mutations, and 4 silent mutations. One patient has two missense mutations at RHD and another two had one missense mutation with one silent mutation. Thirty-one AML1 mutations were detected in 29 of 79 CMML patients (36.7%); 20 patients had 22 mutations located in the N-terminal part and the remaining 9 patients had one single mutation located in the C-terminal region. The patterns of the 31 mutations consisted of 8 missense mutations, 7 nonsense mutations, 15 frameshift mutations and 1 silent mutation. One CMML patient had two missense mutations in RHD and another patient had two frameshift mutations in RHD. Cloning analysis showed that the two mutations were on different alleles in both patients. The frequency of AML1 mutations was significantly higher in patients with CMML than in MDS (P=0.002). Mutations in N-terminal region occurred more frequently in CMML than in MDS (22/30 vs. 8/20, P=0.042). CMML patients had a higher frequency of frameshift mutations as compared with MDS patients (P=0.006). Except for a significantly lower platelet count in CMML patients with AML1 mutations, there were no differences in age, sex, blood counts, percentages of blasts in bone marrow or peripheral blood, subtypes of MDS or CMML, cytogenetic risk groups, time to AML transformation or overall survival between AML1(+) and AML1(−) in MDS and between AML1(+) and AML1(−) CMML patients.

Conclusion: Our results showed that AML1 mutations occurred frequently in both de novo MDS and CMML but with different mutation patterns.

Author notes

Disclosure: No relevant conflicts of interest to declare.