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Hypoxia-induced p38 MAPK activation reduces Mcl-1 expression and facilitates sensitivity towards BH3 mimetics in chronic lymphocytic leukemia

Leukemia volume 29, pages 981–984 (2015)Cite this article

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Chronic lymphocytic leukemia (CLL) is characterized by a distinct chemoresistance, which is thought to be caused by microenvironmental stimulation. In particular, the pivotal role of environmental survival cues involving signaling downstream to CD40 or B-cell receptor in CLL survival and chemoresponse is well characterized.1 In contrast, despite its evident importance in solid tumors,2 the impact of hypoxia on CLL is only poorly understood. Recent reports showed that oxygen levels are reduced down to 1% O2 within bone marrow and spleen,3, 4 indicating its relevance for disease maintenance and progression in hematological malignancies. Here, we show how hypoxia alters the chemoresponse of primary CLL cells and how activation of p38 mitogen-activated protein kinase under hypoxic conditions regulates Mcl-1 expression.

The efficacy of BH3 mimetics depends on the expression levels of antiapoptotic Bcl-2 proteins, especially Bcl-2, BclXL and Mcl-1.6 Therefore, we hypothesized that efficient killing by ABT-737 and ABT-199 under hypoxic conditions is due to deregulation of these Bcl-2 family members. Analysis of the protein expression by immunoblot revealed that Bcl-2 expression was not altered under hypoxic conditions, the protein level was neither altered by CD40L stimulation nor by low oxygen levels (Figure 1c, Supplementary Figure 4A). In contrast, BclXL was strongly induced by CD40 activation, nevertheless this induction was significantly attenuated under hypoxia (Figure 1c, Supplementary Figure 4B). Mcl-1 has repeatedly been shown to promote resistance to BH3 mimetics.7 Importantly, we found all primary CLL samples cultured in hypoxia to express lower levels of Mcl-1 than their normoxic counterparts (Figure 1c, Supplementary Figure 4C), providing a feasible explanation for the increased efficacy of ABT-737 and ABT-199.

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Acknowledgements

We are grateful to Julia Claasen (University Hospital Cologne, Cologne, Germany) for excellent technical support. This work was supported by the Volkswagenstiftung (Lichtenberg Program, HCR), the Deutsche Forschungsgemeinschaft (KFO-286 to HCR, MH, HK and CPP, and RE2246/2-1 to HCR), the Helmholtz-Gemeinschaft (PCCC to HCR) and the Deutsche Jose Carreras Stiftung (DJCLS-R12/26 to HCR and LPF). This study was also in part supported by the German Cancer Aid (DKH109159: lipid metabolism and signaling as new targets in CLL) to CPP and CMW and supported by grants from the Deutsche Forschungsgemeinschaft (DFG: Excellence Cluster 229: Cellular Stress Responses in Aging-Associated Diseases/CECAD; Bonn, Germany) to MH, CMW and LPF. CMW is supported by the CLL Global Research Foundation (Houston, TX, USA).

Author contributions

LPF and CMW conceived and designed the present work; MFH, MP, LB, KB, TO, JF, HJB, ST, MvB-B, CPP and RPZ performed the research; MFH and LPF conducted statistical analysis; MFH, HK, HCR, MH, CMW and LPF analysed the data; MFH and LPF wrote the manuscript. LPF and CMW contributed equally to this work.

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Author notes

  1. C M Wendtner and L P Frenzel: These authors contributed equally to this work.

Authors and Affiliations

  1. Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany,

    M F Huelsemann, M Patz, L Beckmann, H J Becker, S Theurich, M von Bergwelt-Baildon, C P Pallasch, H C Reinhardt, M Hallek, C M Wendtner & L P Frenzel

  2. Center of Integrated Oncology, University Hospital of Cologne, Cologne, Germany,

    M F Huelsemann, M Patz, L Beckmann, H J Becker, S Theurich, M von Bergwelt-Baildon, C P Pallasch, H C Reinhardt, M Hallek, C M Wendtner & L P Frenzel

  3. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University Hospital of Cologne, Cologne, Germany,

    M F Huelsemann, M Patz, L Beckmann, K Brinkmann, C P Pallasch, H Kashkar, H C Reinhardt, M Hallek, C M Wendtner & L P Frenzel

  4. Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, Cologne, Germany

    K Brinkmann & H Kashkar

  5. Institute of Physiology, University of Duisburg-Essen, Essen, Germany

    T Otto & J Fandrey

  6. Leibniz-Institute for Analytical Sciences–ISAS–e.V., Dortmund, Germany

    R P Zahedi

  7. Department I of Internal Medicine, Klinikum Schwabing, Munich, Germany

    C M Wendtner

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  1. M F Huelsemann
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Correspondence to L P Frenzel.

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Huelsemann, M., Patz, M., Beckmann, L. et al. Hypoxia-induced p38 MAPK activation reduces Mcl-1 expression and facilitates sensitivity towards BH3 mimetics in chronic lymphocytic leukemia. Leukemia 29, 981–984 (2015). https://doi.org/10.1038/leu.2014.320

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