High expression of EVI1 and MEL1 is a compelling poor prognostic marker of pediatric AML

Leukemia (2015) 29, 10761083 2015 Macmillan Publishers Limited All rights reserved 0887-6924/15

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ORIGINAL ARTICLE

High expression of EVI1 and MEL1 is a compelling poor prognostic marker of pediatric AML

A Jo1,13, S Mitani1, N Shiba2,3, Y Hayashi2, Y Hara2,3, H Takahashi4, I Tsukimoto5, A Tawa6, K Horibe7, D Tomizawa8, T Taga9, S Adachi10, T Yoshida1 and H Ichikawa1,11,12

EVI1 and MEL1 are homolog genes whose transcriptional activations by chromosomal translocations are known in small subsets of leukemia. From gene expression proling data of 130 Japanese pediatric acute myeloid leukemia (AML) patients, we found that EVI1 and MEL1 were overexpressed in ~ 30% of patients without obvious translocations of these gene loci, and that their high expression was signicantly associated with inferior survival. High EVI1 expression was detected mainly in myelomonocytic-lineage (designated as e-M4/M5 subtype) leukemia with MLL rearrangements and in megakaryocytic-lineage (designated as e-M7 subtype) leukemia, and its prognostic association was observed in the e-M4/M5 subtype but not in the e-M7 subtype. On the other hand, high MEL1 expression was detected in myelocytic-lineage (designated as e-M0/M1/M2 subtype) and e-M4/M5 subtype leukemia without MLL rearrangements, and its prognostic association was independent from the subtypes. Because of their subtype-dependent and mutually exclusive expression, a combined evaluation of their high expression enabled a clear distinction of patients with inferior survival (Po0.00001 in event-free survival (EFS) and overall survival (OS)). This association was conrmed by quantitative reverse transcription PCR analysis of an independent cohort of 81 patients (P = 0.00017 in EFS, P = 0.00028 in OS). We propose that the

combined estimation of EVI1 and MEL1 expression will be an effective method to predict the prognosis of pediatric AML.

Leukemia (2015) 29, 10761083; doi:http://dx.doi.org/10.1038/leu.2015.5

Web End =10.1038/leu.2015.5

INTRODUCTIONAcute myeloid leukemia (AML) is a heterogeneous disease with a variety of genetic alterations and a distinct prognosis. It has become clear that specic chromosomal abnormalities and gene mutations are its most important prognostic markers and therefore useful for stratication of patients to risk-adapted therapeutic strategies.1,2 In pediatric AML, almost the same chromosomal abnormalities and gene mutations are observed and associated with survival as those in adult AML, while their frequencies often differ between adult and pediatric patients.3 In a Japanese clinical study of risk-adapted therapy of...