Bone marrow microenvironment-derived signals induce Mcl-1 dependence in multiple myeloma.
Multiple myeloma is highly dependent on the bone marrow microenvironment until progressing to very advanced extramedullary stages of the disease such as plasma cell leukemia. Stromal cells in the bone marrow secrete a variety of cytokines that promote plasma cell survival by regulating antiapoptotic members of the Bcl-2 family including Mcl-1, Bcl-xL, and Bcl-2. Although the antiapoptotic protein on which a cell depends is typically consistent among normal cells of a particular phenotype, Bcl-2 family dependence is highly heterogeneous in multiple myeloma. Although normal plasma cells and most multiple myeloma cells require Mcl-1 for survival, a subset of myeloma is codependent on Bcl-2 and/or Bcl-xLWe investigated the role of the bone marrow microenvironment in determining Bcl-2 family dependence in multiple myeloma. We used the Bcl-2/Bcl-xLinhibitor ABT-737 to study the factors regulating whether myeloma is Mcl-1 dependent, and thus resistant to ABT-737-induced apoptosis, or Bcl-2/Bcl-xLcodependent, and thus sensitive to ABT-737. We demonstrate that bone marrow stroma is capable of inducing Mcl-1 dependence through the production of the plasma cell survival cytokine interleukin-6 (IL-6). IL-6 upregulates Mcl-1 transcription in a STAT3-dependent manner, although this occurred in a minority of the cells tested. In all cells, IL-6 treatment results in posttranslational modification of the proapoptotic protein Bim. Phosphorylation of Bim shifts its binding from Bcl-2 and Bcl-xLto Mcl-1, an effect reversed by MEK inhibition. Blocking IL-6 or downstream signaling restored Bcl-2/Bcl-xLdependence and may therefore represent a clinically useful strategy to enhance the activity of Bcl-2 inhibitors.
Department of Hematology and Medical Oncology, and.
Vikas A
VA
Gupta
Department of Hematology and Medical Oncology, and.
Shannon M
SM
Matulis
Cancer Biology Graduate Program, Winship Cancer Institute of Emory University, Atlanta, GA.
Jason E
JE
Conage-Pough
Department of Hematology and Medical Oncology, and.
Ajay K
AK
Nooka
Department of Hematology and Medical Oncology, and.
Jonathan L
JL
Kaufman
Department of Hematology and Medical Oncology, and.
Sagar
S
Lonial
Department of Hematology and Medical Oncology, and.
Lawrence H
LH
Boise
D000072224:Bcl-2-Like Protein 11 / Q000235:genetics / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D059016:Tumor Microenvironment; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
C501332:ABT-737; C000595707:BCL2 protein, human; C494811:BCL2L1 protein, human; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds; C508600:IL6 protein, human; D015850:Interleukin-6; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013449:Sulfonamides; D051020:bcl-X Protein