Oncogene-Independent Adaptation Of Pre-B Cell Receptor Signaling Confers Drug Resistance And Signaling Plasticity In Ph-Like All

Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype occurring in 15-40% of older children, adolescents, and adults with B-ALL and is associated with high relapse rates and poor survival. Approximately 50% of Ph-like ALL cases have CRLF2 (cytokine receptor-like factor 2 rearrangements (CRLF2-R), often with concomitant JAK2 point mutations. We and others have shown that targeted inhibition of JAK/STAT and PI3K/AKT signaling in CRLF2-rearranged Ph-like ALL only partially inhibits leukemia proliferation. Our preliminary data indicates that modified B cell receptor signaling results in ERK activation and Ph-like ALL cell growth that appears independent of CRLF2-activated signaling. This study aimed to define the extent to which BCR signaling mediates drug resistance in Ph-like ALL after cytokine receptor signaling inhibition and to develop novel combinatorial treatment strategies.