Bcl‐2 proteins in development, health, and disease of the hematopoietic system

Abstract

Members of the Bcl‐2 protein family regulate cell fate decisions following a variety of developmental cues or stress signals, with the outcomes of cell death or survival, thus shaping multiple mammalian tissues. This review describes in detail how anti‐ and proapoptotic Bcl‐2 proteins contribute to the development and functioning of the fetal and adult hematopoietic systems and how they influence the generation and maintenance of different hematopoietic lineages. An overview on how stress signals such as genotoxic stress or inflammation can compromise blood cell production, partially by engaging the intrinsic apoptosis pathway, is presented. Finally, the review describes how Bcl‐2 protein deregulation—either leading to increased apoptosis resistance or excessive cell death—contributes to many hematological disorders, with specific focus on rare disorders of hematopoiesis and how this knowledge may be used therapeutically.

Human monocytic myeloid‐derived suppressor cells impair B‐cell phenotype and function in vitro

“…In contrast, Bcl‐2 is a pro‐survival effector . According to literature, the tightly regulated balance between pro‐ and anti‐apoptotic Bcl‐2 proteins in the cell decides whether apoptosis is initiated or not . Hence, we suggest that the upregulation of Bcl‐2 might be a compensatory mechanism, counteracting the induction of the death factor BAX in B cells upon M‐MDSCs co‐culture.…”

Programmed Cell Death Deregulation in BCR-ABL1-Negative Myeloproliferative Neoplasms

“…During erythropoiesis, erythropoietin (EPO) ensures erythroid progenitor survival, proliferation, and differentiation by acting on its cognate receptor (EPO-R) and inducing JAK2-STAT5 activation that leads to upregulation of BCL-xL [10]. The development, maturation, and survival of megakaryocytes (MKC) is strictly dependent on the presence of both BCL-xL and MCL-1 proteins that are induced by thrombopoietin (TPO) signaling and restrain intrinsic apoptosis, while platelet life span seems to be dictated only by BCL-xL levels [7,15,16]. Similarly, MCL-1 is essential for granulocyte progenitor survival and differentiation [16].…”

“…The development, maturation, and survival of megakaryocytes (MKC) is strictly dependent on the presence of both BCL-xL and MCL-1 proteins that are induced by thrombopoietin (TPO) signaling and restrain intrinsic apoptosis, while platelet life span seems to be dictated only by BCL-xL levels [7,15,16]. Similarly, MCL-1 is essential for granulocyte progenitor survival and differentiation [16]. On the other hand, the receptor/ligand interactions of the TNF family represent physiological mechanisms that exert a negative regulation in the terminal stages of the hematopoietic differentiation, controlling in this way the size of the expanding hematopoietic clones and maintaining heterogeneity in response to various demands [17].…”

Integrating Ligand and Target-Driven Based Virtual Screening Approaches With in vitro Human Cell Line Models and Time-Resolved Fluorescence Resonance Energy Transfer Assay to Identify Novel Hit Compounds Against BCL-2

“…Apoptosis is a molecular pathway that results with self-destruction of the cell, either following termination of physiological function or after a crucial damage to genetic material (Igney and Krammer, 2002;Reed, 2002;Verma et al, 2015). The well-defined basic apoptosis pathways, extrinsic and the intrinsic pathways, are variously stimulated, and they use determined signaling elements (Kollek et al, 2016). The extrinsic pathway is activated by outer stimulation of death receptors.…”