Biology subjects

Baruchel, A.

Publications and source records attributed to Baruchel, A..

3 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↗

bioRxiv2025

Targeting glucocorticoid-induced CD20 activation in preclinical models of B-ALL

Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is effectively controlled with contemporary multi-agent chemotherapy, resulting to 5-year survival rates above 90%. However, relapse occurs in 15-20% of patients due to minimal residual disease (MRD), characterized by the presence of persisting and resistant leukemic cells, and associated with a poor clinical outcome. Despite its prognostic relevance, the molecular features driving MRD are poorly characterized. In this study, we developed patient-derived xenograft (PDX) models from matched diagnosis and relapse B-ALL samples combined to chemotherapy to mimic MRD in vivo. Drug-tolerant leukemic cells were profiled using single-cell RNA sequencing and we identified a transcriptionally distinct MRD-like population enriched for cell-quiescence, inflammatory stress, and B-cell receptor pathway signatures. Strikingly, the B-lymphocyte surface antigen CD20, encoding by MS4A1 gene, emerged as a consistent upregulated marker in MRD cells from PDXs and patients with diverse oncogenic subtypes. We further demonstrated that CD20 expression is induced by glucocorticoid exposure, creating a therapeutic opportunity where anti-CD20 monoclonal antibodies selectively eradicated MRD cells in vivo. Our data highlight CD20 not only as a biomarker but as an actionable vulnerability in B-ALL MRD, supporting clinical evaluation of anti-CD20 immunotherapy during induction treatment to kill drug-resistant cells and reduce relapse risk.

cancer biology↗

bioRxiv2024

CAR-T cells targeting CCR9 and CD1a for the treatment of T cell acute lymphoblastic leukemia

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy characterized by high rates of induction failure and relapse, and effective targeted immunotherapies are lacking. Despite promising clinical progress with genome-edited CD7-directed CAR-T cells, which present significant logistical and regulatory issues, CAR-T cell therapy in T-ALL remains challenging due to the shared antigen expression between malignant and healthy T cells. This can result in CAR-T cell fratricide, T cell aplasia, and the potential for blast contamination during CAR-T cell manufacturing. Recently, CAR-T cells have been described that target non-pan-T antigens, absent on healthy T cells but expressed on specific T-ALL subsets. These antigens include CD1a (NCT05679895), which is expressed in cortical T-ALL, and CCR9. We show that CCR9 is expressed on >70% of T-ALL patients (132/180) and is maintained at relapse, with a safe expression profile in healthy hematopoietic and non-hematopoietic tissues. Further analyses showed that dual targeting of CCR9 and CD1a could benefit [~]86% of patients with T-ALL, with a greater blast coverage than single CAR-T cell treatments. We therefore developed, characterized, and preclinically validated a novel humanized CCR9-specific CAR with robust and specific antileukemic activity as a monotherapy in vitro and in vivo against cell lines, primary T-ALL samples, and patient-derived xenografts. Importantly, CCR9/CD1a dual-targeting CAR-T cells showed higher efficacy than single-targeting CAR-T cells, particularly in T-ALL cases with phenotypically heterogeneous leukemic populations. Dual CCR9/CD1a CAR-T therapy may prevent T cell aplasia and obviate the need for allogeneic transplantation and regulatory-challenging genome engineering approaches in T-ALL.

immunology↗