BCL-XL expression is essential for human erythropoiesis and engraftment of hematopoietic stem cells

Abstract

The anti-apoptotic BCL-2 proteins (BCL-2, BCL-XL, MCL-1, A1, BCL-W) counteract apoptotic signals emerging during development and under stress conditions, and are thus essential for the survival of every cell. While the "BCL-2 addiction" of different cell types is well described in mouse models, there is only limited information available on the role of different anti-apoptotic BCL-2 proteins in a given human cell type. Here we characterize the role of BCL-XL for survival and function of human hematopoietic cells, with the aim to predict hematological side effects of novel BCL-XL-inhibiting BH3-mimetics and to identify hematological malignancies potentially responsive to such inhibitors. Earlier clinical studies have shown that the combined BCL-2/BCL-XL/BCL-W inhibitor, Navitoclax (ABT-263) induces severe thrombocytopenia caused by direct platelet demise and counteracted by increased megakaryopoiesis. In contrast, murine studies have reported important contribution of BCL-XL to survival of late erythroid cells and megakaryocytes. Using lentiviral knockdown, we show that the roles of BCL-XL for human hematopoietic cells are much more pronounced than expected from murine data and clinical trials. Efficient genetic or chemical BCL-XL inhibition resulted in significant loss of human erythroid cells beginning from very early stages of erythropoiesis, and in a reduction of megakaryocytes. Most importantly, BCL-XL deficient human hematopoietic stem cells and multipotent progenitors were reduced in numbers, and they showed a severely impaired capacity to engraft in mice during xenotransplantation. BCL-XL deficiency was fully compensated by BCL-2 overexpression, however, loss of its antagonist BIM did not result in any rescue of human erythroid or stem and progenitor cells. We thus conclude that novel and specific BCL-XL inhibitors might be efficient to treat malignancies of erythroid or megakaryocytic origin, such as polycythemia vera, acute erythroid leukemia, essential thrombocytosis or acute megakaryocytic leukemia. At the same time, it can be expected that they will have more severe hematological side effects than Navitoclax.

Regulation of Platelet Production and Life Span: Role of Bcl-xL and Potential Implications for Human Platelet Diseases

“…Thus, future studies are needed to gain mechanistic insights into how the described conditions influence platelet production. A recent paper reported a major role for Bcl-xL in human erythropoieisis and hematopoietic stem cells [ 77 ]; they also reported that Bcl-xL knockdown negatively impacted human megakaryocyte survival, albeit not significantly. Our unpublished results confirm that Bcl-xL knockdown impair human megakaryocyte survival, at early and later stages of their differentiation (personal data).…”

Erythroid differentiation in mouse erythroleukemia cells is driven via actin filament-tropomodulin3-tropomyosin networks

“…Bcl-2 proteins have also been shown to have a direct link to actin-mediated apoptosis as the pro-survival Bcl-X L protein suppresses apoptosis induced via cytochalasin D in Jurkat cells (48). Moreover, increased Bcl-X L expression is required for survival of differentiating erythroid cells (49). One can speculate that loss of an actin capping protein such as Tmod3 might act as a trigger for activation of signaling cascades leading to abrogation of increase in Bcl-X L expression, culminating in erythroid cell death.…”

Mitochondrial Kinases and the Role of Mitochondrial Protein Phosphorylation in Health and Disease

“…Bcl-xL is a critical anti-apoptotic protein that plays a role in normal embryogenesis, human erythropoiesis and promotes the survival of differentiating pancreatic cells [ 357 , 358 , 359 ]. Apoptosis is promoted when Bcl-xL residues Thr47 and Thr115 are phosphorylated in human myeloid leukemia cells by stress-activated JNK [ 360 ].…”