All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit the International Myeloma Foundation or HealthTree for Multiple Myeloma.

The Multiple Myeloma Hub uses cookies on this website. They help us give you the best online experience. By continuing to use our website without changing your cookie settings, you agree to our use of cookies in accordance with our updated Cookie Policy

Introducing

Now you can personalise
your Multiple Myeloma Hub experience!

Bookmark content to read later

Select your specific areas of interest

View content recommended for you

Find out more
  TRANSLATE

The Multiple Myeloma Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the Multiple Myeloma Hub cannot guarantee the accuracy of translated content. The Multiple Myeloma Hub and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.

Steering CommitteeAbout UsNewsletterContact
LOADING
You're logged in! Click here any time to manage your account or log out.
LOADING
You're logged in! Click here any time to manage your account or log out.
2017-04-11T08:56:19.000Z

The bone marrow microenvironment drives Mcl-1 dependence

Apr 11, 2017
Share:

Bookmark this article

Crosstalk between Multiple Myeloma (MM) cells and bone marrow (BM) cells is critical for disease maintenance and progression, and therefore understanding the mechanism of this crosstalk is likely to provide clues for future therapeutic targets. In a recent article published in Blood in April 2017 by Vikas Gupta and colleagues from the Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, USA, MM cells were shown to strongly depend on expression of Mcl-1, which in turn was driven by signals emanating from Interleukin-6 (IL-6) secreted from BM stromal cells. Targeting IL-6 removed Mcl-1 dependence and sensitized MM cells to inhibitors of Bcl-2 and Bcl-2/Bcl-xL.

Key Results:

  • Stromal cells were found to confer resistance to the Bcl-2/Bcl-xL inhibitor ABT-737, when incubated with either BM aspirates or CD138+ purified PCs
  • Human cell lines corroborated this finding, and conditioned medium from stromal cells also conferred ABT-737 resistance
  • The stromal-derived soluble component was identified as IL-6 since addition of soluble IL-6 protected cells from ABT-737 and anti-IL-6 neutralizing antibody reversed the effect
  • IL-6 was found to increase dependence on Mcl-1 via ‘Bim priming’ - posttranslational modifications that increase binding of Bim to Mcl-1 and decrease binding to Bcl-2/Bcl-xL
  • Experiments to investigate signaling events downstream of IL-6 indicated that IL-6 governs Bim binding via a MEK-dependent mechanism, independent of Mcl-1 expression levels
  • Inhibition of MEK by U0126 led to increased the levels of Bim associated with Bcl-2/Bcl-xL, and decreased Mcl-1/Bim complexes; JAK inhibition also reversed the protective effect of IL-6, presumably by blocking the initial activation step (prior to MEK activation)
  • Although MM cells are often Mcl-1 dependent, differences were observed between MM cell lines, suggesting that a subset of MM cells are Bcl-2 dependent, especially patient-derived cells with the t(11:14) translocation

In conclusion, soluble IL-6 secreted from stromal cells is a dominant factor regulating Bcl-2 family dependence. This study, therefore, provides a rationale for a treatment regimen in which IL-6 inhibitors (such as siltuxumab) and JAK and/or MEK inhibitors (such as trametinib) are given to enhance Bcl-2 dependence, and are also combined with a specific Bcl-2 inhibitor, such as venetoclax. It will be intriguing to see data from future trials to assess these combined regimens.  

 
  1. Gupta VA. et al. Bone marrow microenvironment-derived signals induce Mcl-1 dependence in multiple myeloma. Blood. 2017 Apr 6;129(14):1969-1979. DOI: 10.1182/blood-2016-10-745059. Epub 2017 Feb 1.

Newsletter

Subscribe to get the best content related to multiple myeloma delivered to your inbox