The novel ZBTB5::JAK2 fusion gene reveals a new mechanism of kinase activation in Ph-like acute lymphoblastic leukemia

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a distinct subtype of B-ALL, exhibiting a kinase-activated gene expression profile similar to Philadelphia chromosome-positive (Ph+) ALL, yet lacking the BCR::ABL fusion. Despite the identification of numerous genetic aberrations and chromosomal rearrangements, particularly those involving the ABL-class or CRLF2/JAK pathways, as drivers and therapeutic targets, the genetic diversity and underlying pathogenic mechanisms of Ph-like ALL remain incompletely understood, posing challenges for diagnosis and treatment. Here, we identified a novel JAK2 fusion, ZBTB5::JAK2, in a Ph-like ALL patient, accompanied by a frequent KRAS12D mutation. Single-cell RNA sequencing (scRNA-seq) analysis suggests that the cell population with both high JAK2 and RAS signals may represent the leukemia stem cells in this patient. To better understand molecular characteristics and pathogenic mechanisms of Ph-like ALL, we performed scRNA-seq on all leukocytes isolated from patients’ PB at initial diagnosis and complete remission (after CART treatment).