Concise Review: Cheating Death for a Better Transplant

Afreen, Sehar; Weiss, Julia Miriam; Strahm, Brigitte; Erlacher, Miriam

doi:10.1002/stem.2901

Cited by 12 publications

(8 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found earlier that both transplantation and xenotransplantation-associated apoptosis are mediated primarily by the BH3-only proteins BIM and BMF 24 . Even their transient inhibition during the period of transplantation and early engraftment resulted in better transplantation outcomes 51,52 . We, therefore, postulated that additional inhibition of BIM would at least partially improve human engraftment during xenotransplantation but, unexpectedly, did not observe any beneficial effects of this manipulation.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this perspective, we suggest that p53 GOF is a non-cellautonomous phenomenon, which would make this gene very peculiar if compared with other oncogenes/oncosuppressors, such as KRas 59,60 , Rb 61,62 or Bcl-2 [63][64][65][66][67] . The p53 mutant can dictate instructions to the microenvironment, which in turn are influenced by additional extrinsic factors that direct signals on the cancer cells that are differentially integrated based on the p53 mutational status (Fig.…”

Section: Conclusion: P53 Mutants: One Gene Many Proteins In Many Conmentioning

confidence: 99%

Context is everything: extrinsic signalling and gain-of-function p53 mutants

Amelio

Melino

2020

Cell Death Discov.

View full text Add to dashboard Cite

The TP53 genomic locus is a target of mutational events in at least half of cancers. Despite several decades of study, a full consensus on the relevance of the acquisition of p53 gain-of-function missense mutants has not been reached. Depending on cancer type, type of mutations and other unidentified factors, the relevance for tumour development and progression of the oncogenic signalling directed by p53 mutants might significantly vary, leading to inconsistent observations that have fuelled a long and fierce debate in the field. Here, we discuss how interaction with the microenvironment and stressors might dictate the gain-of-function effects exerted by individual mutants. We report evidence from the most recent literature in support of the context dependency of p53 mutant biology. This perspective article aims to raise a discussion in the field on the relevance that context might have on p53 gain-offunction mutants, assessing whether this should generally be considered a cell non-autonomous process. Facts • Mutant p53 GOF effects have been shown to vary in different settings, potentially depending on cancer types, experimental models and conditions. • Reciprocal interaction between microenvironment and mutant p53 GOF effects exists.

show abstract

“…We have already showed that inhibition of the intrinsic apoptosis pathway in donor cells, even when limited to a few days around transplantation, significantly improves outcome of HSCT, especially when only low donor cell numbers are available. 18,22,23…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo evaluation of possible pro-survival activities of PGE2, EGF, TPO and FLT3L on human hematopoiesis

et al. 2018

Self Cite

View full text Add to dashboard Cite

Myelosuppression is a major and frequently dose-limiting side effect of anticancer therapy and is responsible for most treatment-related morbidity and mortality. In addition, repeated cycles of DNA damage and cell death of hematopoietic stem and progenitor cells, followed by compensatory proliferation and selection pressure, lead to genomic instability and pave the way for therapy-related myelodysplastic syndromes and secondary acute myeloid leukemia. Protection of hematopoietic stem and progenitor cells from chemo- and radiotherapy in patients with solid tumors would reduce both immediate complications and long-term sequelae. Epidermal growth factor (EGF) and prostaglandin E2 (PGE2) were reported to prevent chemo- or radiotherapy-induced myelosuppression in mice. We tested both molecules for potentially protective effects on human CD34 + cells in vitro and established a xenograft mouse model to analyze stress resistance and regeneration of human hematopoiesis in vivo . EGF was neither able to protect human stem and progenitor cells in vitro nor to promote hematopoietic regeneration following sublethal irradiation in vivo . PGE2 significantly reduced in vitro apoptotic susceptibility of human CD34 + cells to taxol and etoposide. This could, however, be ascribed to reduced proliferation rather than to a change in apoptosis signaling and BCL-2 protein regulation. Accordingly, 16,16-dimethyl-PGE2 (dmPGE2) did not accelerate regeneration of the human hematopoietic system in vivo . Repeated treatment of sublethally irradiated xenograft mice with known antiapoptotic substances, such as human FLT3L and thrombopoietin (TPO), which suppress transcription of the proapoptotic BCL-2 proteins BIM and BMF, also only marginally promoted human hematopoietic regeneration in vivo .

show abstract

Concise Review: Cheating Death for a Better Transplant

Cited by 12 publications

References 88 publications

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

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

Context is everything: extrinsic signalling and gain-of-function p53 mutants

In vitro and in vivo evaluation of possible pro-survival activities of PGE2, EGF, TPO and FLT3L on human hematopoiesis

Contact Info

Product

Resources

About