@article{Dima El-Sharkawi_Duncan Sproul_Christopher G. Allen_Andrew Feber_Melissa Wright_Robert K. Hills_David C. Linch_Rosemary E. Gale_2017, place={Pavia, Italy}, title={Variable outcome and methylation status according to CEBPA mutant type in double-mutated acute myeloid leukemia patients and the possible implications for treatment}, volume={103}, url={https://haematologica.org/article/view/8327}, DOI={10.3324/haematol.2017.173096}, abstractNote={Although <em>CEBPA</em> double-mutated (<em>CEBPA</em><sup>DM</sup>) acute myeloid leukemia is considered to be a favorable-risk disease, relapse remains a major cause of treatment failure. Most <em>CEBPA</em><sup>DM</sup> 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 (<em>CEBPA</em><sup>Classic-DM</sup>), 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 <em>CEBPA</em><sup>DM</sup> patients, 79 <em>CEBPA</em><sup>Classic-DM</sup> and 25 with non-classic mutants, and found that the latter may have poorer survival (5-year overall survival 64% <em>vs.</em> 46%; <em>P</em>=0.05), particularly post relapse (41% <em>vs.</em> 0%; <em>P</em>=0.02). However, for this analysis, all non-classic cases were grouped together, irrespective of mutant combination. As <em>CEBPA</em><sup>DM</sup> cases have been reported to be hypermethylated, we used methylation profiling to assess whether this could segregate the different mutants. We developed a <em>CEBPA</em><sup>Classic-DM</sup> methylation signature from a preliminary cohort of 10 <em>CEBPA</em><sup>DM</sup> (including 8 <em>CEBPA</em><sup>Classic-DM</sup>) and 30 <em>CEBPA</em> wild-type (<em>CEBPA</em><sup>WT</sup>) samples, and independently validated the signature in 17 <em>CEBPA</em><sup>Classic-DM</sup> cases. Assessment of the signature in 16 <em>CEBPA</em><sup>DM</sup> cases with different non-classic mutant combinations showed that only 31% had a methylation profile equivalent to <em>CEBPA</em><sup>Classic-DM</sup> whereas for 69% the profile was either intermediate between <em>CEBPA</em><sup>Classic-DM</sup> and <em>CEBPA</em><sup>WT</sup> or equivalent to <em>CEBPA</em><sup>WT</sup>. These results suggest that <em>CEBPA</em><sup>DM</sup> cases with non-classic mutants may be functionally different from those with <em>CEBPA</em><sup>Classic-DM</sup> mutants, and should not automatically be included in the same prognostic group. (AML12 is registered under <a class="external-ref external-ref-type-isrctn" href="/external-ref?link_type=ISRCTN&amp;access_num=ISRCTN17833622">ISRCTN17833622</a> and AML15 under <a class="external-ref external-ref-type-isrctn" href="/external-ref?link_type=ISRCTN&amp;access_num=ISRCTN17161961">ISRCTN17161961</a&gt;).}, number={1}, journal={Haematologica}, author={Dima El-Sharkawi and Duncan Sproul and Christopher G. Allen and Andrew Feber and Melissa Wright and Robert K. Hills and David C. Linch and Rosemary E. Gale}, year={2017}, month={Dec.}, pages={91-100} }