title: ALL-associated JAK1 mutations confer hypersensitivity to the antiproliferative effect of type I interferon.
abstract: Activating mutations in JAK1 have been reported in acute lymphoblastic leukemias (ALLs). In this study, we found a type I interferon (IFN) transcriptional signature in JAK1 mutation-positive human ALL samples. 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 because 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 JAK1(A634D) was abrogated by type I IFNs. Interestingly, we found that different JAK1 mutations differentially potentiate responses to type I IFNs or to interleukin-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 JAK1(A634D) are hypersensitive to the antiproliferative and antitumorigenic effect of type I IFN, suggesting that type I IFNs should be considered as a potential therapy for ALL with JAK1-activating mutations.
authors.affiliation: Ludwig Institute for Cancer Research, Brussels, Belgium.
authors.forename: Tekla
authors.initials: T
authors.lastname: Hornakova
authors.forename: Sabina
authors.initials: S
authors.lastname: Chiaretti
authors.forename: Muriel M
authors.initials: MM
authors.lastname: Lemaire
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
authors.forename: Raouf
authors.initials: R
authors.lastname: Ben Abdelali
authors.forename: Vahid
authors.initials: V
authors.lastname: Asnafi
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Renauld
authors.forename: Laurent
authors.initials: L
authors.lastname: Knoops
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002986:Clinical Trials as Topic; D005260:Female; D015870:Gene Expression; D006801:Humans; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D007370:Interferon Type I; C507904:JAK1 protein, human; D053613:Janus Kinase 1