Activated interleukin-7 receptor signaling drives B-cell acute lymphoblastic leukemia in mice.

Abstract

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype of B-ALL often associated with genetic variants that alter cytokine receptor signaling, including mutations in the interleukin-7 receptor (IL7R). Although gain-of-function mutations in IL7R are present in a subset of Ph-like ALLs, whether these lesions can initiate leukemic disease remains unknown. To investigate whether IL7R variants are leukemia-initiating, we built mouse models expressing activated Il7r (aIL7R). B-cell intrinsic aIL7R mice developed spontaneous B-ALL, demonstrating sufficiency of Il7r activating mutations in leukemogenesis. Concomitant introduction of a knock-out allele in the associated adapter protein Lnk (encoded by Sh2b3) or a dominant-negative variant of the transcription factor Ikaros (Ikzf1) increased disease penetrance. The resulting murine leukemias displayed monoclonality and recurrent somatic Kras mutations and efficiently engrafted into immunocompetent mice. Prior to transformation, aIL7R-expressing mice exhibited an expansion of late pro-B cells with elevated Bcl-xl expression and IL-7-independent survival. Phosphoproteomic analyses of aIL7R leukemic cells revealed constitutive Stat5 signaling and B cell receptor (BCR)-like signaling despite absence of surface pre-BCR. A human Ph-like ALL xenograft with mutant IL7R, loss of SH2B3, and VPREB1 deletion recapitulated this signature. Finally, in vitro treatment of aIL7R leukemic B-cells with Jak, mTOR, or Syk inhibitors blocked growth, confirming that each pathway is active in this model of IL7R-driven B-ALL.