The bone marrow microenvironment drives Mcl-1 dependence

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-x_L.

Key Results:

• Stromal cells were found to confer resistance to the Bcl-2/Bcl-x_L 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-x_L
• 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-x_L, 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.