Abstract
The acquisition of growth signal self-sufficiency is 1 of the hallmarks of cancer. We previously reported that the murine interleukin-9-dependent TS1 cell line gives rise to growth factor-independent clones with constitutive activation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. Here, we show that this transforming event results from activating mutations either in JAK1, JAK3, or in both kinases. Transient and stable expression of JAK1 and/or JAK3 mutants showed that each mutant induces STAT activation and that their coexpression further increases this activation. The proliferation of growth factor-independent TS1 clones can be efficiently blocked by JAK inhibitors such as ruxolitinib or CMP6 in short-term assays. However, resistant clones occur upon long-term culture in the presence of inhibitors. Surprisingly, resistance to CMP6 was not caused by the acquisition of secondary mutations in the adenosine triphosphate-binding pocket of the JAK mutant. Indeed, cells that originally showed a JAK1-activating mutation became resistant to inhibitors by acquiring another activating mutation in JAK3, whereas cells that originally showed a JAK3-activating mutation became resistant to inhibitors by acquiring another activating mutation in JAK1. These observations underline the cooperation between JAK1 and JAK3 mutants in T-cell transformation and represent a new mechanism of acquisition of resistance against JAK inhibitors.
| Original language | English |
|---|---|
| Pages (from-to) | 3924-3931 |
| Number of pages | 8 |
| Journal | Blood |
| Volume | 124 |
| Issue number | 26 |
| DOIs | |
| Publication status | Published - Dec 18 2014 |
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ASJC Scopus subject areas
- Hematology
- Biochemistry
- Cell Biology
- Immunology
- Medicine(all)
Cite this
Cooperating JAK1 and JAK3 mutants increase resistance to JAK inhibitors. / Springuel, Lorraine; Hornakova, Tekla; Losdyck, Elisabeth; Lambert, Fanny; Leroy, Emilie; Constantinescu, Stefan N.; Flex, Elisabetta; Tartaglia, Marco; Knoops, Laurent; Renauld, Jean Christophe.
In: Blood, Vol. 124, No. 26, 18.12.2014, p. 3924-3931.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cooperating JAK1 and JAK3 mutants increase resistance to JAK inhibitors
AU - Springuel, Lorraine
AU - Hornakova, Tekla
AU - Losdyck, Elisabeth
AU - Lambert, Fanny
AU - Leroy, Emilie
AU - Constantinescu, Stefan N.
AU - Flex, Elisabetta
AU - Tartaglia, Marco
AU - Knoops, Laurent
AU - Renauld, Jean Christophe
PY - 2014/12/18
Y1 - 2014/12/18
N2 - The acquisition of growth signal self-sufficiency is 1 of the hallmarks of cancer. We previously reported that the murine interleukin-9-dependent TS1 cell line gives rise to growth factor-independent clones with constitutive activation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. Here, we show that this transforming event results from activating mutations either in JAK1, JAK3, or in both kinases. Transient and stable expression of JAK1 and/or JAK3 mutants showed that each mutant induces STAT activation and that their coexpression further increases this activation. The proliferation of growth factor-independent TS1 clones can be efficiently blocked by JAK inhibitors such as ruxolitinib or CMP6 in short-term assays. However, resistant clones occur upon long-term culture in the presence of inhibitors. Surprisingly, resistance to CMP6 was not caused by the acquisition of secondary mutations in the adenosine triphosphate-binding pocket of the JAK mutant. Indeed, cells that originally showed a JAK1-activating mutation became resistant to inhibitors by acquiring another activating mutation in JAK3, whereas cells that originally showed a JAK3-activating mutation became resistant to inhibitors by acquiring another activating mutation in JAK1. These observations underline the cooperation between JAK1 and JAK3 mutants in T-cell transformation and represent a new mechanism of acquisition of resistance against JAK inhibitors.
AB - The acquisition of growth signal self-sufficiency is 1 of the hallmarks of cancer. We previously reported that the murine interleukin-9-dependent TS1 cell line gives rise to growth factor-independent clones with constitutive activation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. Here, we show that this transforming event results from activating mutations either in JAK1, JAK3, or in both kinases. Transient and stable expression of JAK1 and/or JAK3 mutants showed that each mutant induces STAT activation and that their coexpression further increases this activation. The proliferation of growth factor-independent TS1 clones can be efficiently blocked by JAK inhibitors such as ruxolitinib or CMP6 in short-term assays. However, resistant clones occur upon long-term culture in the presence of inhibitors. Surprisingly, resistance to CMP6 was not caused by the acquisition of secondary mutations in the adenosine triphosphate-binding pocket of the JAK mutant. Indeed, cells that originally showed a JAK1-activating mutation became resistant to inhibitors by acquiring another activating mutation in JAK3, whereas cells that originally showed a JAK3-activating mutation became resistant to inhibitors by acquiring another activating mutation in JAK1. These observations underline the cooperation between JAK1 and JAK3 mutants in T-cell transformation and represent a new mechanism of acquisition of resistance against JAK inhibitors.
UR - http://www.scopus.com/inward/record.url?scp=84919474961&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84919474961&partnerID=8YFLogxK
U2 - 10.1182/blood-2014-05-576652
DO - 10.1182/blood-2014-05-576652
M3 - Article
C2 - 25352124
AN - SCOPUS:84919474961
VL - 124
SP - 3924
EP - 3931
JO - Blood
JF - Blood
SN - 0006-4971
IS - 26
ER -