Biology subjects

Gachet, S.

Publications and source records attributed to Gachet, S..

4 recordsLinked to original sources

bioRxiv2026

In vivo isogenic modelling unveils a TP53-mediated relapse phenotype in T-cell acute lymphoblastic leukemia

Many patients with T-cell acute lymphoblastic leukemia (T-ALL) relapse into a treatment-resistant disease. The mechanisms driving relapse remain largely elusive, in part due to the lack of faithful experimental models. Here, we leveraged patient-derived xenograft (PDX) pairs generated from diagnosis and relapse T-ALLs to functionally address the cellular mechanisms driving TP53-altered relapse. Beyond inter-T-ALL variability, comparative analyses revealed a unique, cell-intrinsic relapse phenotype that includes greater leukemia-initiating capacity and that can be conferred to diagnosis cells by TP53 silencing. Transcriptomic profiling linked the relapse phenotype to deregulated OXPHOS metabolism and MYC signaling. Integration of single-cell profilings uncovered TP53-wildtype cell populations at diagnosis expressing a relapse profile, possibly reflecting a pre-existing modulation of TP53 signaling. These cells sequentially evolved towards biallelic TP53 inactivation at relapse. Collectively, our findings support a model in which T-ALL relapses emerge from a selected pre-existing transcriptional state characterized by deregulated metabolism that favors subsequent TP53 inactivation.

cancer biology↗

bioRxiv2026

Transplantation in neonate mouse recipients enhances umbilical cord blood CD34+ cells permissiveness to ETO2::GLIS2-driven transformation

Acute megakaryoblastic leukemia (AMKL) is a rare and aggressive pediatric acute myeloid leukemia subtype, frequently driven by the ETO2::GLIS2 (EG) gene fusion in de novo AMKL patients. The EG fusion confers poor prognosis and high relapse risk. In a previous study, we demonstrated that human fetal hematopoietic cells are intrinsically permissive to EG-driven transformation and that microenvironmental cues critically enhance leukemogenesis in less permissive human cord blood (CB) cells. However, most pediatric AML models are established in adult recipient mice, potentially overlooking developmental niche-specific effects. Here, we investigated whether mouse neonates provide a more permissive environment for EG-driven leukemogenesis from human CB hematopoietic stem and progenitor cells (HSPCs). Comparison of xenotransplants of EG-transduced CB CD34+ cells into sublethally irradiated NSG neonate or adult mice show that neonatal recipients are more supportive of EG-driven leukemia when cell doses are adjusted for recipient size. Neonates exhibited a higher frequency of leukemia-initiating cells (LIC), enhanced expansion of EG/GFP+ leukemic cells, and increased disease penetrance compared with adults at similar dose/size ratio, despite similar overall human hematopoietic engraftment. Leukemic cells arising in neonates and adults displayed comparable phenotypes and secondary transplantation capacities, indicating functional equivalence. Both CD34+CD38- and CD34+CD38+ CB subpopulations were sensitive to EG-driven transformation, with neonates consistently showing higher LIC frequencies than adults. Together, our findings demonstrate that the developmental stage of the host microenvironment is a critical extrinsic determinant of EG-mediated leukemogenesis. Neonatal recipients constitute a physiologically relevant and highly sensitive model for studying pediatric AMKL initiation with low cell inputs, enabling refined investigation of microenvironmental signals that promote leukemia development and may reveal novel therapeutic vulnerabilities

cancer biology↗

bioRxiv2022

Urbanisation impacts the diversity, coloration, and body size of wild bees in a Mediterranean city

Urbanisation is a growing phenomenon causing the decline of wild bees globally. Yet, bees manage to persist in the urban matrix thanks to islands of vegetation in public parks and private gardens. While we begin to comprehend the impact of urbanisation on bees diversity and abundance, our understanding of its impact on the functional diversity of wild bees is limited. Here, we use an integrative approach to investigate the response of wild bees to urbanisation at the community, species, and individual levels. To do so, we sampled wild bees in 24 public parks along an urbanisation gradient in the Mediterranean city of Marseille. We found that species richness and abundance decreased in more urbanised areas, but increased in larger city parks. Moreover, larger individuals within species, but not larger species, were found in larger city parks, suggesting that park size is crucial for the persistence of bees in cities. Interestingly, we show that brighter species were found in parks surrounded by a large amount of impervious surface, highlighting the importance of colour traits in the response to environmental changes. Finally, our results revealed that larger species, but not larger individuals, were also more colourful. In summary, our study not only confirmed that urbanisation negatively impacts community-level traits, but that it also affects species coloration and individuals body size, thus improving our understanding of the functional response of wild bees to urbanisation. We suggest that increasing park size may compensate for the negative effects of urbanisation on wild bees.

ecology↗

bioRxiv2020

NFAT are Essential and Redundant Actors for Leukemia Initiating Potential in T-cell Acute Lymphoblastic Leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy with few available targeted therapies. We previously reported that the phosphatase calcineurin (Cn) is required for LIC (leukemia Initiating Capacity) potential of T-ALL pointing to Cn as an interesting therapeutic target. Calcineurin inhibitors have however unwanted side effect. NFAT transcription factors play crucial roles downstream of calcineurin during thymocyte development, T cell differentiation, activation and anergy. Here we elucidate NFAT functional relevance in T-ALL. Using murine T-ALL models in which Nfat genes can be inactivated either singly or in combination, we show that NFATs are required for T-ALL LIC potential and essential to survival, proliferation and migration of T-ALL cells. We also demonstrate that Nfat genes are functionally redundant in T-ALL and identified a node of genes commonly deregulated upon Cn or NFAT inactivation, which may serve as future candidate targets for T-ALL.

cancer biology↗