Ricerc@Sapienza

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease comprising several molecularly defined subgroups. Among these, the BCR/ABL1-like (alias Philadelphia-like) subset has been recognized by gene expression profiling: it displays a transcriptional profile that resembles that of true BCR/ABL1-positive cases, contains activating tyrosine kinase lesions and JAK/STAT mutations, and is associated with a poor outcome. The genomic background varies from case to case, thus making the design of a single diagnostic assay difficult. Our group (Chiaretti et al, 2018) recently generated a tool, named BCR/ABL1-like predictor, for the identification of these cases at diagnosis. This tool is economic and quick. If applied at diagnosis, it may prompt the design of novel treatment schemes, including the upfront use of a tyrosine kinase inhibitor (TKI), aimed at improving the outcome of adult BCR/ABL1-like ALL patients.
In this study, we will apply the BCR/ABL1-like predictor to all newly-diagnosed cases enrolled in the front-line GIMEMA trial LAL1913 - based on a pediatric-inspired chemotherapy scheme and further intensified according to the levels of minimal residual disease (MRD) - as well as in the forthcoming trial LAL2317, based on the same backbone but implemented with blinatumomab, a bispecific monoclonal antibody.
Besides confirming the incidence, clinical features and outcome of this subset, the project aims at refining the molecular landscape of BCR/ABL1-like ALL cases by using RNA-sequencing, mutational screening and copy number aberrations (CNA) analysis to gain a deeper insight in the underlying lesions, with the final goal of further stratifying this group of patients from a molecular and clinical standpoint. It is likely that this subgroup includes cases with a different prognostic likelihood. Finally, we will further confirm the reproducibility of this approach through international collaborations based on sample sharing and sample retesting.