Biology subjects

Marchand, T.

Publications and source records attributed to Marchand, T..

5 recordsLinked to original sources

bioRxiv2025

Signals from the bone marrow B cell niches shape pre-leukemic fate in murine B cell acute lymphoblastic leukemia

The bone marrow (BM) microenvironment plays a key role in supporting B cell development. In acute lymphoblastic leukemia (B-ALL), the acquisition of oncogenic driver mutations blocks B cell differentiation at specific stages. When these pre-leukemic cells acquire secondary mutations, B-ALL develops. However, the role of the BM microenvironment in pre-leukemic cell fate remains unknown. Here, using a murine model of spontaneous B-ALL development, we show that disrupted pre-BCR signaling in pre-leukemic cells modifies their fate. Blocking expression of the pre-BCR ligand Galectin-1 by the microenvironment impaired pre-leukemic cell proliferation and leukemia-initiating capacity. Consequently, B-ALL development was delayed, and B-ALL had a more mature phenotype, with cells expressing a BCR. Secondary mutations were also altered by changes to Galectin-1 expression, in its absence mutations almost exclusively affected IL-7R signaling rather than both pre-BCR and IL-7R signaling. These results show that signals from BM niches can directly influence pre-leukemic B cell fate.

cancer biology↗

bioRxiv2024

FedPyDESeq2: a federated framework for bulk RNA-seq differential expression analysis

Large-scale transcriptomic studies are often limited by data silos and risks of privacy leakage, which may lead to missed clinical insights. Meta-analysis methods may be used to aggregate local results, but they induce lower statistical power and are particularly sensitive to heterogeneous settings. A recent paradigm in distributed computing, federated learning (FL) is a means of fitting models from siloed data, while ensuring that private data does not leave its storage facilities. Here, we introduce FedPyDESeq2, a software for differential expression analysis (DEA) on siloed bulk RNA-seq. Building on FL tools, FedPyDESeq2 implements the DESeq2 pipeline for DEA on siloed datasets in a privacy-enhancing manner. We benchmark FedPyDESeq2 on datasets from The Cancer Genome Atlas corresponding to 8 different indications, split by geographical origin. FedPyDESeq2 achieves near-identical results on siloed data compared with PyDESeq2 on pooled data, and significantly outperforms meta-analysis baselines.

bioinformatics↗

bioRxiv2023

High CD44 expression identifies rare chemoresistant leukemic cells endowed with enhanced E-Selectin binding in T-ALL

T-cell acute lymphoblastic leukemia (T-ALL) is a hematopoietic malignancy characterized by an increased proliferation and incomplete maturation of T-cell progenitors. Despite therapeutic improvements, relapses are often of bad prognosis. Therapeutic vulnerabilities and chemoresistance mechanisms arising from cell plasticity induced by the bone marrow (BM) microenvironment remain an important field of investigation. Employing single cell RNA sequencing (scRNAseq) of human T-ALL cells recovered from adipocyte-rich and -poor BM, a distinct leukemic stem cell (LSC) population defined by quiescence and elevated CD44 level (Ki67neg/lowCD44high) expression is identified in both territories. In vivo chemotherapy demonstrated that the LSC population evades drug treatment. Patient sample analyses confirmed the presence of Ki67neg/lowCD44high LSC both at diagnosis and relapse that displayed a specific transcriptomic signature. Interestingly, the intense expression of CD44 in T-ALL Ki67neg/lowLSC was associated with E-selectin binding. Importantly, when 39 human T-ALL samples were analyzed, the E-selectin binding ability was found significantly higher in Relapse/Refractory compared to drug-sensitive patients. These findings characterize a T-ALL LSC population with chemoresistant properties and shade light on new strategies for prognostic stratification while opening avenues for novel therapeutic options.

cancer biology↗

bioRxiv2023

Haematopoietic stem cell numbers are not solely determined by niche availability

Haematopoietic stem cells (HSCs) reside in specialized microenvironments, also referred to as niches, and it has been widely believed that HSC numbers are determined by the niche size alone1-5. However, the vast excess of the number of niche cells over that of HSCs raises questions about this model. We initially established a mathematical model of niche availability and occupancy, which predicted that HSC numbers are restricted at both systemic and local levels. To address this question experimentally, we developed a femoral bone transplantation system, enabling us to increase the number of available HSC niches. We found that the addition of niches does not alter total HSC numbers in the body, regardless of whether the endogenous (host) niche is intact or defective, suggesting that HSC numbers are limited at the systemic level. Additionally, HSC numbers in transplanted wild-type femurs did not increase beyond physiological levels when HSCs were mobilized from defective endogenous niches to the periphery, indicating that HSC numbers are also constrained at the local level. Our study demonstrates that HSC numbers are not solely determined by niche availability, thereby rewriting the long-standing model for the regulation of HSC numbers.

cell biology↗

bioRxiv2023

Periosteal skeletal stem cells can migrate into the bone marrow and support hematopoiesis after injury

Skeletal stem cells have been isolated from various tissues, including periosteum and bone marrow, where they exhibit key functions in bone biology and hematopoiesis, respectively. The role of periosteal skeletal stem cells in bone regeneration and healing has been extensively studied, but their ability to contribute to the bone marrow stroma is still under debate. In the present study, we characterized a whole bone transplantation model that mimics the initial bone marrow necrosis and fatty infiltration seen after injury. Using this model and a lineage tracing approach, we observed the migration of periosteal skeletal stem cells into the bone marrow after transplantation. Once in the bone marrow, periosteal skeletal stem cells are phenotypically and functionally reprogrammed into bone marrow mesenchymal stem cells that express high levels of hematopoietic stem cell niche factors such as Cxcl12 and Kitl. In addition, using ex vivo and in vivo approaches, we found that periosteal skeletal stem cells are more resistant to acute stress than bone marrow mesenchymal stem cells. These results highlight the plasticity of periosteal skeletal stem cells and their potential role in bone marrow regeneration after bone marrow injury.

cell biology↗