# Hematopoietic stem/progenitor cell transplantation recovers immune defects and prevents lymphomas in Atm-deficient mice

## TL;DR

Transplanting healthy stem cells into mice lacking the ATM protein helps restore immune function and prevents lymphomas, offering hope for treating Ataxia-telangiectasia.

## Contribution

This study shows that HSPC transplantation can rescue immune defects and prevent cancer in Atm-deficient mice.

## Key findings

- Transplanted HSPCs restored T and B cell function in Atm-deficient mice.
- DNA damage response was re-established in transplanted mice.
- HSPC transplantation prevented thymoma development in Atm−/− mice.

## Abstract

Ataxia-telangiectasia (A-T) is a rare autosomal recessive multi-system and life-shortening disease, characterized by progressive cerebellar neurodegeneration, immunodeficiency, radiation sensitivity and cancer predisposition, with high incidence of leukemia and lymphoma. A-T is caused by mutations in the gene encoding for ATM protein that has a major role in maintaining the integrity of the genome. Because there are no cures for A-T, we aimed to tackle immunodeficiency and prevent cancer onset/progression by transplantation therapy.

Enriched hematopoietic stem/progenitor cells (HSPCs), collected from bone marrow of wild-type mice, were transplanted in the caudal vein of 1 month old conditioned Atm−/− mice.

Genomic analyses showed that transplanted Atm positive cells were found in lymphoid organs. B cells isolated from spleen of transplanted mice were able to undergo class switching recombination. Thymocytes were capable to correctly differentiate and consequently an increase of helper T cells and TCRβhi expressing cells was observed. Protein analysis of isolated T and B cells from transplanted mice, revealed that they expressed Atm and responded to DNA damage by initiating an Atm-dependent phosphorylation cascade. Indeed, aberrant metaphases were reduced in transplanted Atm-deficient mice. Six months after transplantation, Atm−/− mice showed signs of aging, but they maintained the rescue of T cells maturation, showed DNA damage response, and prevented thymoma.

We can conclude that wild-type enriched HSPCs transplantation into young Atm-deficient mice can ameliorate A-T hematopoietic phenotypes and prevent tumor of hematopoietic origin.

The online version contains supplementary material available at 10.1186/s40164-024-00544-0.