Variable outcome and methylation status according to CEBPA mutant type in double-mutated acute myeloid leukemia...

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).