Characterisation of a convergent malignant phenotype in B-cell acute lymphoblastic leukaemia

Adria Closa0, Marina Reixachs0, Eduardo Eyras0
(0) JCSMR

Find me on Wed Nov 25th, 1:30-2:50pm AEDT in Remo, table 100

Abstract
Acute lymphoblastic leukaemia (ALL) is the most common form of cancer in children worldwide. Although combination chemotherapy provides in general an effective treatment, resulting in an overall survival of >90%, subtypes of paediatric ALL affecting children in the first year of life or carrying rearrangements of the mixed lineage leukaemia (MLL) gene remain with a dismal prognosis. These poor outcomes highlight the unmet need for a better understanding of the molecular mechanisms of acute leukaemia and motivate the search for new therapeutic strategies for high- risk paediatric acute leukaemia. Genome sequencing studies of ALL patients have shown a very low frequency of somatic mutations, indicating that MLL-r may not require additional alterations to induce full transformation. However, the mechanisms of how gene fusions relate to disease transformation remain to be fully explained. To uncover new molecular mechanisms potentially linked to the observed poor outcome, we performed an exhaustive multicohort analysis of gene-fusions and RNA processing alterations in 428 B-ALL patients.
We identified 84 fusions with significant allele frequency across patients, 6 of them novel and 19 known from other blood and solid tumours but which had not been observed before in ALL. We have analysed and uncovered the similarities in their potential functional impacts.
Furthermore, using MLL-r and ETV6-r as proxies for high and low risk, respectively, we found an expression signature involving MYC target genes and regulators of RNA processing in association with MLL-r patients. Moreover, this signature has a predictive power related with risk in an independent set of patients with other or no fusions, demonstrated by a Random Forest model of survival and a Cox-regression test. This risk signature includes the upregulation of the splicing factor SRRM1, which we show that through the interaction with other splicing factors potentially impact a set of alternative splicing events associated with high risk.

Our findings provide evidence for a convergent mechanism of aberrant RNA processing that sustains a malignant phenotype in a subset of gene-fusion-driven B-ALL cases. This convergent phenotype can complement the risk diagnosis currently based on gene-fusion detection.