To study the mutational landscape of AML at relapse we sequenced 261 samples at diagnosi and after disease reoccurrence.. longitudinal study of the mutational landscape of AML at relapse

Genomic characteristics of AML is becoming one of the most important aspect in the clinical routine at diagnosis, but less is understood about molecular pattern at recurrence after chemotherapy (CT) and allogeneic stem cell transplantation (HSCT). To identify players in tumor evolutions and in distinct relapse models we performed a wide targeted sequencing (192 genes) of 200 samples at different time points with focus of relapse after HSCT (n=84 diagnosis, n=54 relapses after CT, n=71 relapses after HSCT) and in particular of relapse with genomic loss of mismatched HLA haplotype (HLA loss) (n=31). Mutational landscape at diagnosis and the high association of FLT3-ITD with relapses (p=xxx) appeared to be similar to previously published datasets (Pearson Score =xx). A strong association of mutation in WT1 with relapse after CT (p=xx) and HSCT (p=xxx) was identified. Among the genes with known oncogenic potential, it was impossible to identify a mutations or a functional category more represented in the HLA loss relapses. In contrast, the group of DNA damage related gene, known to be tumor suppressor and cancer regulators, were significantly more mutated in the HLA loss group (p=xxx). We could be able to identify at least two cases in which the immune escape determined by loss of HLA in a subclone of the leukemia led to an abrupt clonal evolution with loss of biologically relevant clones harbouring BCOR, MLL-PTD, WT1, KRAS and NRAS mutations. Although still in need of confirmation on a larger cohort, our results demonstrate that a different pattern of mutations could lead to particular escape from immune pressure of HSCT.