Cell death pathways in lymphoid malignancies
Fletcher L, Nabrinsky E, Liu T, Danilov A. Cell Death Pathways in Lymphoid Malignancies. Curr Oncol Rep. 2020;22(1):10. doi: 10.1007/s11912-020-0874-3.
PURPOSE OF REVIEW: This review highlights the importance of the Bcl-2 family members in lymphoma cell survival and discusses the approaches to modulate their function, directly or indirectly, to advance lymphoma therapeutics.
RECENT FINDINGS: The balance of cell death versus survival is ultimately leveraged at the mitochondria. Mitochondrial outer membrane permeabilization (MOMP) is the critical event that governs the release of pro-apoptotic molecules from the intermembrane mitochondrial space. MOMP is achieved through the coordinated actions of pro- and anti-apoptotic Bcl-2 family member proteins. Recognition of functional alterations among the Bcl-2 family member proteins led to identification of tractable targets to combat hematologic malignancies. A new class of drugs, termed BH3 mimetics, was introduced in the clinic. Venetoclax, a Bcl-2 inhibitor, received regulatory approvals in therapy of chronic lymphocytic leukemia and acute myeloid leukemia. Alternative pro-survival Bcl-2 family proteins, in particular Mcl-1, have been successfully targeted in preclinical studies using novel-specific BH3 mimetics. Finally, anti-apoptotic Bcl-2 family members may be targeted indirectly, via interference with the pro-survival signaling pathways, e.g., phosphoinotiside-3 kinase, B-cell receptor signaling, and NF-κB.