ALL-Associated JAK1 Mutations Confer Hypersensitivity to the Anti-Proliferative Effect of Type I Interferon.

Abstract 3066

Poster Board III-3

Recently, we and others reported activating mutations in JAK1 in acute lymphoblastic leukemia (ALL). These mutations are relatively common in adult patients with T cell ALL. JAK1 is a tyrosine kinase that associates to different cytokine receptors to mediate signal transduction. The associations of the mutant JAK1 with receptors like IL-2R or IL-9R are necessary to promote tumorigenicity by inducing constitutive signaling via the activation of the receptor complex. Because JAK1 mutations confer poor prognosis to the patients, there is a need for new therapies that could specifically target the leukemic blast.

Starting from patient samples, we show here that JAK1-mutant ALL blasts are characterized by a type-I interferon (IFN) transcriptional signature. This signature was recapitulated in vitro by the expression of JAK1 mutants in BW5147 and BaF3 hematopoietic cell lines. Binding of JAK1 to the IFN receptor was essential since mutations in the FERM domain abrogated this effect. Beside the constitutive activation of the type I IFN signaling cascade, JAK1 mutations also strongly potentiated the response to IFN in vitro. Typically, the proliferation of cell lines expressing JAK1A634D was abrogated by type I IFNs. Interestingly, we found that different JAK1 mutations differentially potentiate responses to type I IFNs or to IL-9, another cytokine using JAK1 to mediate its effects. This suggests that the type of mutation influences the specificity of the effect on distinct cytokine receptor signaling. Finally, we also showed in an in vivo leukemia model that cells expressing JAK1A634D are hypersensitive to the anti-proliferative and anti-tumorigenic effect of type I IFN, suggesting that type I IFNs should be considered as a potential therapy for ALL with JAK1 activating mutations.