Bone marrow microenvironment- induced regulation of Bcl-2 family members in multiple myeloma (MM): Therapeutic implications

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 antiapoptotic 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.

Automated summary

In Multiple Myeloma (MM), the disruption of the bone marrow microenvironment leads to the evasion of apoptosis by cancer cells. The MM BM milieu, consisting of cytokines, growth factors, intercellular and cell: ECM interactions, and exosomes, contributes to the abundance of pro-survival Bcl-2 family members in tumor cells. Advances in molecular knowledge have resulted in the development of small molecules that mimic BH3-only proteins, which show promise as therapeutic strategies to target Bcl-2 family members. Modifying the tumor microenvironment to indirectly activate apoptotic pathways is also being explored. This review summarizes our current understanding of the molecular mechanisms underlying MM tumor cell evasion from apoptosis, as well as potential therapeutic strategies to overcome Bcl-2-mediated tumor cell survival.