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

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). 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. Phosphoproteomic analyses of aIL7R leukemic cells revealed constitutive Stat5 signaling and B cell receptor (BCR)-like signaling despite the absence of surface pre-BCR. 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 mouse model of IL7R-driven B-ALL.

Automated summary

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype of B-ALL often associated with genetic variants altering cytokine receptor signaling, such as mutations in the interleukin-7 receptor (IL7R). Mouse models expressing activated Il7r (aIL7R) demonstrated that Il7r activating mutations are sufficient for leukemogenesis, with additional mutations in associated adapter protein Lnk or transcription factor Ikaros increasing disease penetrance. Phosphoproteomic analyses revealed constitutive Stat5 and BCR-like signaling in aIL7R leukemic cells, and inhibition of Jak, mTOR, or Syk pathways blocked growth in vitro.