Insights into the biological determinants of clonal evolution and therapeutic vulnerabilities of del(11q) chronic lymphocytic leukemia
Miguel Quijada Álamo
Centro de Investigación del Cáncer, CIC-IBMCC
Chromosome 11q22.3 deletion -del(11q)- is one of the most common cytogenetic alterations in chronic lymphocytic leukemia (CLL), which defines a high-risk subgroup of patients characterized by a rapid disease progression, impaired responses to chemotherapy-based regimes and reduced survival. The size of this deletion is variable and it can encompass hundreds of genes, being specifically ATM and BIRC3 suggested to have a role in CLL pathogenesis, since loss-of-function mutations of ATM or BIRC3 preferentially occur in del(11q) cases. This complete dysfunction of ATM or BIRC3 proteins has been shown to aggravate the outcome of del(11q) patients. However, the biological determinants by which the co-occurrence of these abnormalities drives CLL progression, clonal evolution and therapy response are largely unexplored. In addition, other concomitant genetic abnormalities have also been described in del(11q) patients, although their role in the prognosis of this specific subgroup of CLLs has not been established.
To answer these questions, we have used a high-throughput sequencing approach to characterize the mutational landscape of a high-risk cohort of del(11q) CLL patients, and in parallel, we have generated novel in vitro and in vivo models recapitulating the biology of del(11q) as well as concurrent mutations in ATM, BIRC3 or other genes. These models, in combination with ex vivo primary CLL cultures from genetically-matched patients, have made possible to gain a deeper understanding of role of ATM and BIRC3 in del(11q) clonal evolution, as well as to define a novel therapeutic vulnerability of this subgroup of patients to dual BCR and PARP inhibition.