Transient apoptosis inhibition in donor stem cells improves hematopoietic stem cell transplantation

Abstract

Kollek et al. show that transient inhibition of apoptosis by short-term BCL-XL overexpression increases the viability of hematopoietic stem cells (HSCs) during engraftment and improves the outcome of HSC transplantation without signs of adverse pathologies. This strategy represents a promising and novel therapeutic approach, particularly under conditions of limited donor stem cell availability.

Concise Review: Cheating Death for a Better Transplant

“…Both approaches resulted in 6–8 days long apoptosis inhibition in murine HSPCs in vitro. In line with our hypothesis, manipulated murine HSPCs were able to robustly displace the wild‐type cells during competitive reconstitution experiments . Most importantly, recipient mice did not show any signs of disease during the 1‐year post‐transplantation period, and no BCL‐XL overexpressing cells were found 16 weeks after transplantation.…”

“…We speculate that protecting donor HSPCs by BCL‐2/BCL‐XL overexpression might be useful even in the case of FAS‐mediated T cell‐induced apoptosis, since the anti‐apoptotic BCL‐2 proteins inhibit tBID‐induced amplification of the apoptosis signal. Important for all patients, increased viability of HSPCs would be beneficial during storage and transport and accelerate hematopoietic reconstitution, as we observed in our mouse models . We, therefore, conclude that each patient undergoing HSCT could benefit from a shortened time frame of bone marrow aplasia.…”

“…Theoretically, cells with a malignant potential must undergo apoptosis as soon as levels of BCL‐XL, BCL‐2, or BAX/BAK inhibitors plummet. Accordingly, we observed no signs of malignant transformation in our primary and secondary recipients transplanted with short‐term apoptosis resistant HSPCs and, most importantly, no accelerated tumorigenesis on a premalignant background . Nonetheless, we cannot deny the possibility that pre‐malignant HSPCs during the short period of therapeutic apoptosis‐resistance could acquire genetic hits to evade cell death on a long run.…”

“…Most importantly, recipient mice did not show any signs of disease during the 1‐year post‐transplantation period, and no BCL‐XL overexpressing cells were found 16 weeks after transplantation. Even when combined with oncogene activation, transient BCL‐XL overexpression did not accelerate lymphomagenesis . In summary, our data indicate that transient apoptosis inhibition by BCL‐XL overexpression is safe and effective to enhance the fitness of HSPCs during transplantation.…”

“…Viral transduction of HSPCs also leads to activation of p53, resulting in compromised cell recovery and engraftment potential . Indeed, we observed severely impaired engraftment capacity of murine HSPCs infected with control adenoviruses . Other pitfalls of our approach might be the rejection of adenovirally infected donor cells by adenovirus‐specific immune cells of the recipient, the formation of neutralizing antibodies against the TAT peptide or autoantibodies against BCL‐XL as well as insufficient time of action of BAX/BAK inhibitors.…”