El-Sharkawi, D;
Sproul, D;
Allen, CG;
Feber, A;
Wright, M;
Hills, RK;
Linch, DC;
(2018)
Variable Outcome And Methylation Status According To CEBPA Mutant Type In Double-Mutated Acute Myeloid Leukemia Patients And The Possible Implications For Treatment.
Haematologica
, 103
(1)
pp. 91-100.
10.3324/haematol.2017.173096.
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Abstract
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).
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