PhD Defense: ABL family genes in pediatric acute lymphoblastic leukemia; Molecular determinants of tyrosine kinase inhibitor response

The study focuses on ABL-family genes in acute lymphoblastic leukemia (ALL), a prevalent form of blood cancer in children and adults. ALL involving ABL-family fusion genes are chemotherapy-resistant and can be subdivided into BCR::ABL1 subtype and ABL-class subtype. Effective treatment for these ALL subtypes involves tyrosine kinase inhibitors, yet a significant portion of BCR::ABL1 patients remains unresponsive. For the ABL-class subtype, the efficacy of tyrosine kinase inhibitors is only limitedly studied. This research aimed to comprehend tyrosine kinase inhibitor responses in samples taken at initial diagnosis of disease before exposure to tyrosine kinase inhibitors.

In BCR::ABL1, resistance to tyrosine kinase inhibitors correlated with decreased BCR::ABL1 protein activation and heightened B-cell development gene alterations. The ABL-class subtype can be subdivided based on ABL-class kinase into ABL1, ABL2, PDGFRB, or CSF1R-fused leukemias. We observed that the kinase gene in the fusion was the main determinant for TKI response in ABL-class ALL. 

To monitor treatment response by the number of leukemic cells present at various stages of therapy is crucial. We compared direct monitoring of the oncogenic fusion gene with traditional methods monitoring lymphoblasts. Our oncogenic fusion gene-based approach proved successful, particularly in cases lacking suitable markers. Using this approach, we discovered a patient with multi-lineage presentation rather than ALL with implications for better diagnosis and treatment.

In conclusion, the research underscores the need for alternative treatment options in tyrosine kinase inhibitor-resistant ABL-family ALL cases. Overall, the research enhances understanding of the biology and tyrosine kinase inhibitor response in BCR::ABL1 and ABL-class ALL.