TY - JOUR
T1 - Bone marrow microenvironment- induced regulation of Bcl-2 family members in multiple myeloma (MM)
T2 - Therapeutic implications
AU - Aksoy, Osman
AU - Lind, Judith
AU - Sunder-Plaßmann, Vincent
AU - Vallet, Sonia
AU - Podar, Klaus
N1 - Funding Information:
This investigation was supported by the Technopol grant WST3-F-5031298/002-2018 (KP), the WST3-F-5031 298/003-2019 (KP), and the Life Science grant LSC18-010 (SV and KP). KP is the recipient of a research support grant from Roche Pharmaceuticals.
Publisher Copyright:
© 2022 The Author(s)
PY - 2023/1
Y1 - 2023/1
N2 - In Multiple Myeloma (MM) the finely tuned homeostasis of the bone marrow (BM) microenvironment is disrupted. Evasion of programmed cell death (apoptosis) represents a hallmark of cancer. Besides genetic aberrations, the supportive and protective MM BM milieu, which is constituted by cytokines and growth factors, intercellular and cell: extracellular matrix (ECM) interactions and exosomes, in particular, plays a key role in the abundance of pro-survival members of the Bcl-2 family (i.e., Mcl-1, Bcl-2, and Bcl-xL) in tumor cells. Moreover, microenvironmental cues have also an impact on stability- regulating post-translational modifications of anti-apoptotic proteins including de/phosphorylation, polyubiquitination; on their intracellular binding affinities, and localization. Advances of our molecular knowledge on the escape of cancer cells from apoptosis have informed the development of a new class of small molecules that mimic the action of BH3-only proteins. Indeed, approaches to directly target anti-apoptotic Bcl-2 family members are among today's most promising therapeutic strategies and BH3-mimetics (i.e., venetoclax) are currently revolutionizing not only the treatment of CLL and AML, but also hold great therapeutic promise in MM. Furthermore, approaches that activate apoptotic pathways indirectly via modification of the tumor microenvironment have already entered clinical practice. The present review article will summarize our up-to-date knowledge on molecular mechanisms by which the MM BM microenvironment, cytokines, and growth factors in particular, mediates tumor cell evasion from apoptosis. Moreover, it will discuss some of the most promising science- derived therapeutic strategies to overcome Bcl-2- mediated tumor cell survival in order to further improve MM patient outcome.
AB - In Multiple Myeloma (MM) the finely tuned homeostasis of the bone marrow (BM) microenvironment is disrupted. Evasion of programmed cell death (apoptosis) represents a hallmark of cancer. Besides genetic aberrations, the supportive and protective MM BM milieu, which is constituted by cytokines and growth factors, intercellular and cell: extracellular matrix (ECM) interactions and exosomes, in particular, plays a key role in the abundance of pro-survival members of the Bcl-2 family (i.e., Mcl-1, Bcl-2, and Bcl-xL) in tumor cells. Moreover, microenvironmental cues have also an impact on stability- regulating post-translational modifications of anti-apoptotic proteins including de/phosphorylation, polyubiquitination; on their intracellular binding affinities, and localization. Advances of our molecular knowledge on the escape of cancer cells from apoptosis have informed the development of a new class of small molecules that mimic the action of BH3-only proteins. Indeed, approaches to directly target anti-apoptotic Bcl-2 family members are among today's most promising therapeutic strategies and BH3-mimetics (i.e., venetoclax) are currently revolutionizing not only the treatment of CLL and AML, but also hold great therapeutic promise in MM. Furthermore, approaches that activate apoptotic pathways indirectly via modification of the tumor microenvironment have already entered clinical practice. The present review article will summarize our up-to-date knowledge on molecular mechanisms by which the MM BM microenvironment, cytokines, and growth factors in particular, mediates tumor cell evasion from apoptosis. Moreover, it will discuss some of the most promising science- derived therapeutic strategies to overcome Bcl-2- mediated tumor cell survival in order to further improve MM patient outcome.
KW - Apoptosis
KW - Bone Marrow/metabolism
KW - Cell Line, Tumor
KW - Cytokines/metabolism
KW - Family
KW - Humans
KW - Multiple Myeloma/metabolism
KW - Myeloid Cell Leukemia Sequence 1 Protein/chemistry
KW - Proto-Oncogene Proteins c-bcl-2/metabolism
KW - Tumor Microenvironment
KW - bcl-X Protein/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85142457629&partnerID=8YFLogxK
U2 - 10.1016/j.cyto.2022.156062
DO - 10.1016/j.cyto.2022.156062
M3 - Journal article
C2 - 36332463
SN - 1043-4666
VL - 161
SP - 156062
JO - Cytokine
JF - Cytokine
M1 - 156062
ER -