Current prognostic classification of Acute Myeloid Leukemia (AML) is based on cytogenetics and a limited number of mutations, where patients belong either to favorable, intermediate and adverse cytogenetic groups. The majority of patients will be classified into intermediate cytogenetics, an heterogenous group in which clinical outcome is highly variable and for which clinical decisions are difficult. This problem still leads to over- or under-therapy with dire consequences. In addition, a subset of patients with adverse cytogenetics will fail to respond to current therapies. More discriminatory risk stratification will lead to more accurate clinical decisions.
The Leucegene project aims at improving prognostic classification of AML using RNA-sequencing of a large cohort of BCLQ AML samples (n=457) from diverse cytogenetic subgroups. First, detailed mutational analysis is being performed to explore the landscape of known and novel mutations in AML. Transcriptomes are then correlated to clinical, cytogenetic and mutational data to identify the top differentially expressed genes to develop a transcriptomic-based classification.
As an exemple, EVI1-rearranged (EVI1-r) AML are characterized by distinct molecular alterations. We thus performed RNA sequencing of 12 EVI1-r AMLs and compared the results with those of other AML subtypes and normal CD34+ cells. EVI1-r AMLs have recurrent mutations in RAS and other signaling genes, splicing factors, and at a lower frequency, IKZF1 and TP53. EVI1-r AMLs also show a charactheristic transcriptome profile marked by high expression of MECOM, PREX2, MYCT1, PAWR and VIP (Lavallée VP et al. Blood 2015).