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Although CEBPA double-mutated ( CEBPA  DM ) acute myeloid leukemia is considered to be a favorable-risk disease, relapse remains a major cause of treatment failure. Most CEBPA  DM patients have a classic biallelic mutant combination with an N-terminal mutation leading to production of p30 protein plus a C-terminal loss-of-function in-frame indel mutation ( CEBPA  Classic-DM ), but approximately one-third of cases have one or more non-classic mutations, with diverse combinations reported, and there is little information on the consequences of such mutants. We evaluated outcome in a cohort of 104 CEBPA  DM patients, 79 CEBPA  Classic-DM and 25 with non-classic mutants, and found that the latter may have poorer survival (5-year overall survival 64% vs. 46%; P =0.05), particularly post relapse (41% vs. 0%; P =0.02). However, for this analysis, all non-classic cases were grouped together, irrespective of mutant combination. As CEBPA  DM cases have been reported to be hypermethylated, we used methylation profiling to assess whether this could segregate the different mutants. We developed a CEBPA  Classic-DM methylation signature from a preliminary cohort of 10 CEBPA  DM (including 8 CEBPA  Classic-DM ) and 30 CEBPA wild-type ( CEBPA  WT ) samples, and independently validated the signature in 17 CEBPA  Classic-DM cases. Assessment of the signature in 16 CEBPA  DM cases with different non-classic mutant combinations showed that only 31% had a methylation profile equivalent to CEBPA  Classic-DM whereas for 69% the profile was either intermediate between CEBPA  Classic-DM and CEBPA  WT or equivalent to CEBPA  WT These results suggest that CEBPA  DM cases with non-classic mutants may be functionally different from those with CEBPA  Classic-DM mutants, and should not automatically be included in the same prognostic group. (AML12 is registered under ISRCTN17833622 and AML15 under ISRCTN17161961).

haematologica

Variable outcome and methylation status according to <i>CEBPA</i> mutant type in double-mutated acute myeloid leukemia patients and the possible implications for treatment

Variable outcome and methylation status according to CEBPA mutant type in double-mutated acute myeloid leukemia patients and the possible implications for treatment