Tyrosine kinase inhibitor response of ABL-class acute lymphoblastic leukemia: the role of kinase type and SH3 domain

Abstract

Acute lymphoblastic leukemia (ALL) with fusions of ABL-class tyrosine kinase genes other than BCR::ABL1 occurs in approximately 3% of children with ALL. The tyrosine kinase genes involved in this BCR::ABL1-like (Ph-like) subtype include ABL1, PDGFRB, ABL2, and CSF1R, which each have up to ten described partner genes. ABL-class ALL resembles BCR::ABL1-positive ALL by a similar gene expression profile, a poor response to chemotherapy, and sensitivity to tyrosine kinase inhibitors (TKIs). There is a lack of comprehensive data regarding TKI sensitivity for the heterogeneous group of ABL-class ALL. We observed variability in TKI sensitivity both within and amongst each ABL-class tyrosine kinase gene subgroup. We showed that ALL samples with fusions of any of the four tyrosine kinase genes were relatively sensitive to imatinib. In contrast, PDGFRB-fused ALL samples were less sensitive to dasatinib and bosutinib. Variation in ex vivo TKI response within the subset of samples with the same ABL-class tyrosine kinase gene was not associated with ALL immunophenotype, 5' fusion partner, the presence or absence of the Src-homology-2/3 domains, or deletions of IKZF1, PAX5, or CDKN2A/B. In conclusion, the tyrosine kinase gene involved in ABL-class ALL is the main determinant for TKI sensitivity and is relevant for specific TKI selection.