Targeting Senescent Stemlike Subpopulations in Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia.

Philadelphia chromosome-like B-cell acute lymphoblastic leukemia (Ph-like ALL) is driven by genetic alterations that induce constitutive kinase signaling and is associated with chemoresistance and high relapse risk in children and adults. Preclinical studies in the most common CRLF2-rearranged/JAK pathway-activated Ph-like ALL subtype have shown variable responses to JAK inhibitor-based therapies, suggesting incomplete oncogene addiction and highlighting a need to elucidate alternative biologic dependencies and therapeutic vulnerabilities, while the ABL-class Ph-like ALL subtype appears preferentially sensitive to SRC/ABL- or PDGFRB-targeting inhibitors. Which patients may be responsive versus resistant to tyrosine kinase inhibitor (TKI)-based precision medicine approaches remains a critical knowledge gap.