Page 88 - Haematologica-April 2018

O.K. Weinberg et al.
Figure 3. Presence of mutations in de novo acute myeloid leukemia (AML). Analyzed by presence of a subclone.
mutational events.3 In the Papaemmanuil et al. study, mutations in DNMT3A, ASXL1, IDH1/2 and TET2 appeared to be acquired the earliest and were almost never found in isolation, while NPM1 mutations were usually secondary events.24 The only morphological fea- tures we identified to be associated with outcome was the presence of frequent (score ≥3) micromegakaryocytes; a finding that was independent of any mutations or muta- tion pattern. In MDS, Della Porta et al. also found that severity of megakaryocytic dysplasia correlated with out-
come.12 Feng et al. found that micromegakaryocytes were independent prognostic factors and improved predictive accuracy of the International Prognostic Scoring System- revised (IPSS-R) in their study of 422 MDS patients.25 Our results suggest that micromegakaryocytes in de novo AML could represent a better marker for aggressive disease than the traditional WHO definition of multilineage dysplasia that takes into account dyserythropoiesis and dysgranu- lopoiesis, which did not affect outcome in our study. Our findings suggest that some cases currently diagnosed as AML-MRC on the basis of dyserythropoiesis and dysgran- ulopoiesis may not be truly biologically secondary disease and may not be appropriately classified with other AML- MRC cases defined by cytogenetics or history of MDS. Conversely, dysmegakaryopoiesis showed significant associations with specific mutations (when manifesting as forms with separated nuclear lobes) as well as shortened survival (when manifesting as micromegakaryocytes).
Our findings highlight the continued relevance of evalu- ating the background maturing hematopoiesis, specifically megakaryocytes, in de novo AML, even in the current era of detailed mutational analysis. The independent impact of micromegakaryocytes on outcome may reflect factors influencing megakaryocyte morphology that are not directly related to the leukemia mutation pattern, such as epigenetics, the BM microenvironment, or individual patients' characteristics. The finding that a leukemia sub- clone adversely and independently impacted outcome implies that, not only the number and types of mutations, but also the clonal leukemia architecture should be taken into account in future AML risk stratification schemes.
Acknowledgments
The authors would like to thank Susan Wong for her editorial assistance with this work.
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