Targeting the Hidden Survival Mechanism of Pre-Leukemic Cells

Summary

Why do pre-leukemic cells survive for years without becoming cancerous — and sometimes without ever disappearing? This study shows that a specific genetic alteration found in many cases of childhood leukemia, known as ETV6::RUNX1 (E::R), reprograms oncogene-induced senescence (OIS). Instead of halting damaged cells from dividing, it creates a quiescent, stress-resistant cell population that survives DNA damage and persists in the body for years. The findings also highlight senolytic therapies as a promising strategy to selectively eliminate these persistent pre-leukemic cells before leukemia develops.

A protectivemechanism that unexpectedly promotes survival

The aim ofthis study was to determine whether E::R induces OIS, contributing to thelong-term survival of pre-leukemic cells. Using inducible cell models andtransgenic mice expressing E::R, researchers found that pre-leukemic cellsdisplayed the classical hallmarks of cellular senescence.

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Tounderstand why these dormant cells escaped elimination, the team analyzedproteins involved in the cellular stress response using Western blot. Proteinexpression was measured using the Alliance Q9 Advanced imaging system (Uvitec Cambridge),enabling sensitive chemiluminescent detection and reliable proteinquantification.

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Theanalysis showed that E::R activated p53 and drovecells into a senescence-like growth arrest. To test whether p53 could stilltrigger apoptosis after DNA damage, the researchers exposed the cells to aDNA-damaging treatment. While control cells activated the expected apoptoticresponse, E::R- positive cells did not, indicating that they had becomeresistant to apoptosis and could survive despite accumulating genetic damage.

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**Figure** 1. ETV6::RUNX1-positive cells fail to activate the p53 apoptoticresponse after DNA damage

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Western blot analysis comparing p53 phosphorylation after DNA damage in control and E::R-positive cells. Pp53 Ser15 (an early marker of p53 activation) is expressed in both control and E::R-positive cells, showing that both respond to DNA damage. However, pp53 Ser392 (required for p53-mediated apoptosis) is only expressed in control cells but not in E::R-positive cells, indicating that the p53 stress response is activated, but the apoptotic response is not. Image extracted from Acunzo et al., 2026, Cell Death Discovery.

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Targetingsenescence exposes a therapeutic vulnerability

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Theresearchers then explored whether this survival mechanism could also become atherapeutic opportunity.

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Because E::R-positivecells relied on senescence-associated pathways to persist, they tested severalsenolytic compounds designed to selectively eliminate senescent cells. Allthree compounds preferentially eliminated ETV6::RUNX1-positive cells whilelargely sparing control cells. Of which, one was shown to significantly reducepre-B colony formation from pre-leukemic progenitors isolated from transgenicmice, providing proof of principle that senolytic therapies may help eliminatepre-leukemic cells before leukemia develops.

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Conclusion

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This study shows that ETV6::RUNX1 reprograms OIS into a survival mechanism, allowing pre-leukemic cells to resist apoptosis and persist over time. By identifying senescence as a therapeutic vulnerability, the findings highlight the potential of senolytic therapies to eradicate pre-leukemic cells, although further studies will be needed to validate this approach in vivo and in humans.

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Results at a glance

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Finding	Key Result
Cellular phenotype	ETV6::RUNX1 induced a senescence-like state characterized by increased ROS, β-galactosidase activity and inflammatory SASP secretion.
Molecular mechanism	Western blot revealed p53 accumulation but loss of Ser392 phosphorylation, explaining resistance to apoptosis.
Cell Resistance	Pre-leukemic cells showed increased resistance to DNA damage, with up to 1.85-fold enrichment after irradiation.
Therapeutic opportunity	Senolytic compounds (SSK1, piperlongumine and TM5441) selectively eliminated pre-leukemic cells.

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Glossary

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Oncogene-inducedsenescence (OIS): Acellular program in which activation of an oncogene normally halts cellproliferation, acting as a natural barrier against cancer.

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ETV6::RUNX1: A fusion gene generated beforebirth and commonly associated with childhood B-cell acute lymphoblasticleukemia.

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P53: A key protein that helps protect the body bystopping damaged cells from dividing or by triggering apoptosis when DNA damageis too severe.

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Mr. Sacha Sapsford

Sales Director

With over 3 years’ experience in imaging systems and a background in biomedicine, I’m passionate about helping researchers get the most out of their imaging workflows. Fun fact: When I am not busy working, you’ll find me on a bike exploring or trying to find the best coffee shop.