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Author Spotlight: Analyzing Bone Marrow Microenvironment in Murine Hematological Malignancies
Published on: November 10, 2023
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Bone marrow microenvironment-derived signals induce Mcl-1 dependence in multiple myeloma
Vikas A Gupta1, Shannon M Matulis1, Jason E Conage-Pough2
1Department of Hematology and Medical Oncology, and.
Blood
|February 3, 2017
Summary
The bone marrow microenvironment influences multiple myeloma cell survival by altering dependence on antiapoptotic proteins. Blocking interleukin-6 (IL-6) signaling can restore sensitivity to Bcl-2 inhibitors, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Multiple myeloma (MM) cells rely on the bone marrow microenvironment for survival.
- MM cells exhibit heterogeneous dependence on antiapoptotic proteins of the B-cell lymphoma 2 (Bcl-2) family, including Mcl-1, Bcl-xL, and Bcl-2.
- While most MM cells require Mcl-1, some are co-dependent on Bcl-2 and/or Bcl-xL, impacting treatment sensitivity.
Purpose of the Study:
- To investigate how the bone marrow microenvironment dictates Bcl-2 family protein dependence in multiple myeloma.
- To understand the mechanisms by which myeloma cells become resistant to Bcl-2/Bcl-xL inhibitors like ABT-737.
Main Methods:
- Utilized the Bcl-2/Bcl-xL inhibitor ABT-737 to assess myeloma cell sensitivity.
- Investigated the role of bone marrow stromal cells and the cytokine interleukin-6 (IL-6) in regulating Mcl-1 dependence.
- Analyzed the impact of IL-6 on Mcl-1 transcription (STAT3-dependent) and Bim protein phosphorylation (MEK inhibition reversal).
Main Results:
- Bone marrow stroma induces Mcl-1 dependence in myeloma cells via IL-6.
- IL-6 upregulates Mcl-1 transcription in a subset of cells and causes posttranslational modification of Bim.
- Phosphorylation of Bim by IL-6 shifts its binding from Bcl-2/Bcl-xL to Mcl-1, conferring resistance to ABT-737.
- MEK inhibition reversed the effect of IL-6 on Bim phosphorylation.
Conclusions:
- Bone marrow stroma, through IL-6, can drive Mcl-1 dependence in multiple myeloma, leading to resistance to Bcl-2/Bcl-xL inhibitors.
- Blocking IL-6 or its downstream signaling pathways can restore Bcl-2/Bcl-xL dependence.
- Targeting IL-6 signaling may enhance the efficacy of Bcl-2 inhibitors in multiple myeloma treatment.
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