TY - JOUR
T1 - ALL-associated JAK1 mutations confer hypersensitivity to the antiproliferative effect of type I interferon
AU - Hornakova, Tekla
AU - Chiaretti, Sabina
AU - Lemaire, Muriel M.
AU - Foà, Robin
AU - Abdelali, Raouf Ben
AU - Asnafi, Vahid
AU - Tartaglia, Marco
AU - Renauld, Jean Christophe
AU - Knoops, Laurent
PY - 2010/4/22
Y1 - 2010/4/22
N2 - 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 JAK1A634D 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 anti-proliferative 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.
AB - 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 JAK1A634D 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 anti-proliferative 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.
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U2 - 10.1182/blood-2009-09-245498
DO - 10.1182/blood-2009-09-245498
M3 - Article
C2 - 20167706
AN - SCOPUS:77951437714
VL - 115
SP - 3287
EP - 3295
JO - Blood
JF - Blood
SN - 0006-4971
IS - 16
ER -