Bim and Mcl-1 exert key roles in regulating JAK2V617F cell survival
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Rubert, Joelle, Qian, Zhiyan, Andraos, Rita, Guthy, Daniel Alexander and Radimerski, Thomas (2011) Bim and Mcl-1 exert key roles in regulating JAK2V617F cell survival. BMC Cancer, 11. p. 24. ISSN 1471-2407
Abstract
Background: The JAK2V617F mutation plays a major role in the pathogenesis of myeloproliferative neoplasms and
is found in the vast majority of patients suffering from polycythemia vera and in roughly every second patient
suffering from essential thrombocythemia or from primary myelofibrosis. The V617F mutation is thought to provide
hematopoietic stem cells and myeloid progenitors with a survival and proliferation advantage. It has previously
been shown that activated JAK2 promotes cell survival by upregulating the anti-apoptotic STAT5 target gene BclxL.
In this study, we have investigated the role of additional apoptotic players, the pro-apoptotic protein Bim as
well as the anti-apoptotic protein Mcl-1.
Methods: Pharmacological inhibition of JAK2/STAT5 signaling in JAK2V617F mutant SET-2 and MB-02 cells was used to study effects on signaling, cell proliferation and apoptosis by Western blot analysis, WST-1 proliferation assays and flow cytometry. Cells were transfected with siRNA oligos to deplete candidate pro- and anti-apoptotic proteins.
Co-immunoprecipitation assays were performed to assess the impact of JAK2 inhibition on complexes of pro- and
anti-apoptotic proteins.
Results: Treatment of JAK2V617F mutant cell lines with a JAK2 inhibitor was found to trigger Bim activation.
Furthermore, Bim depletion by RNAi suppressed JAK2 inhibitor-induced cell death. Bim activation following JAK2
inhibition led to enhanced sequestration of Mcl-1, besides Bcl-xL. Importantly, Mcl-1 depletion by RNAi was
sufficient to compromise JAK2V617F mutant cell viability and sensitized the cells to JAK2 inhibition.
Conclusions: We conclude that Bim and Mcl-1 have key opposing roles in regulating JAK2V617F cell survival and
propose that inactivation of aberrant JAK2 signaling leads to changes in Bim complexes that trigger cell death.
Thus, further preclinical evaluation of combinations of JAK2 inhibitors with Bcl-2 family antagonists that also tackle Mcl-1, besides Bcl-xL, is warranted to assess the therapeutic potential for the treatment of chronic
myeloproliferative neoplasms.
| Item Type: | Article |
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| Date Deposited: | 13 Oct 2015 13:16 |
| Last Modified: | 13 Oct 2015 13:16 |
| URI: | https://oak.novartis.com/id/eprint/3206 |