Biology subjects

Marty, C.

Publications and source records attributed to Marty, C..

3 recordsLinked to original sources

bioRxiv2026

Fibronectin silencing remodels the fibrotic bone marrow niche

Bone marrow (BM) fibrosis is a defining feature of Primary Myelofibrosis, yet the extracellular matrix (ECM) that sustains the fibrotic niche remains largely untargeted therapeutically. Fibronectin (FN), a key organizer of ECM architecture and growth factor signaling, accumulates in the fibrotic BM niche and correlates with disease severity. Here, we investigated whether systemic FN depletion can disrupt pathological remodeling of the BM niche. We developed a chemically modified antisense oligonucleotide targeting FN1 (FN ASO), which reduced FN expression and assembly and impaired transforming growth factor-{beta}1 (TGF-{beta}1)-induced activation of mesenchymal stromal cells. Systemic FN ASO administration efficiently depleted circulating and BM FN in mice and was well tolerated during short-term treatment. In two complementary models of BM fibrosis, FN silencing reduced FN matrix organization, stromal activation, active TGF{beta}-1, reticulin, and collagen deposition. In Jak2V617F-driven disease, transcriptomic profiling further revealed attenuation of ECM, TGF-{beta}1, and mesenchymal remodeling programs, accompanied by changes in inflammatory signaling. Collectively, these findings identify FN as an active organizer of the fibrotic BM niche and show that its systemic silencing uncouple ECM organization from profibrotic stromal signaling, providing rationale for targeting FN in myelofibrosis with broader therapeutic relevance to fibrosis-driven diseases.

cancer biology↗

bioRxiv2026

CAR T cell therapy selectively depletes disease-driving mutant calreticulin cells in xenotransplants and human organoid models of myelofibrosis

Targeted immunotherapies have revolutionized outcomes for lymphoid malignancies, but success in myeloid neoplasms is limited by the lack of amenable targets and immunologically hostile tumor microenvironment (TME). Myeloproliferative neoplasms are chronic myeloid blood cancers, a third of which are driven by mutations in calreticulin (mutCALR). This yields a common neoepitope that binds to, and activates, the thrombopoietin receptor and results in display of the oncoprotein on the extracellular membrane of disease-driving cells, exposing a therapeutic vulnerability. Here, we present a first-in-class chimeric antigen receptor (CAR) T-cell therapy that specifically targets mutCALR+ cells, both in vitro and in vivo. The CAR T-cell therapy selectively depleted mutCALR+ stem cells from patients with myelofibrosis while sparing healthy stem cells, and improved survival in mutCALR leukemia xenografts. To mimic myelofibrotic marrow, we developed a bespoke human chimeroid model and showed no decrease in the potency of CAR T cell-mediated target cell killing even in a fibrotic tumor microenvironment. We also devised a method to boost cell surface expression of mutCALR in CD34+ cells isolated from patients with accelerated/blast phase MPN (defined as >10 % blasts in peripheral blood or bone marrow), enhancing CAR T targeting. This study presents a therapeutic with potential to eradicate mutCALR-driven malignancies and highlights an innovative strategy to evaluate blood cancer-targeting immunotherapies in a relevant TME. One Sentence SummaryA first-in-class CAR T-cell therapy targeting mutant calreticulin selectively depletes malignant stem cells in vivo and in fibrotic human organoids.

cancer biology↗

bioRxiv2022

ANKRD26 is a new regulator of type I cytokine receptor signaling in normal and pathological hematopoiesis

Sustained ANKRD26 expression associated with germline ANKRD26 mutations causes Thrombocytopenia 2 (THC2), an inherited platelet disorder associated with leukemia predisposition. Some of those patients present also erythrocytosis and/or leukocytosis. Using multiple human-relevant in vitro models (cell lines, primary patient cells and patient-derived iPSCs) we demonstrate for the first time that ANKRD26 is expressed during the early steps of erythroid, megakaryocyte and granulocyte differentiation, and is necessary for progenitor proliferation. As differentiation progresses, ANKRD26 expression is progressively silenced, to complete the cellular maturation of the three myeloid lineages. In primary cells, abnormal ANKRD26 expression in committed progenitors directly impacts the proliferation/differentiation balance for these three cell types. We show that ANKRD26 interacts with and crucially modulates the activity of MPL, EPOR and G-CSFR, three homodimeric type I cytokine receptors that regulate blood cell production. Higher than normal levels of ANKRD26 prevent the receptor internalization, which leads to increased signaling and cytokine hypersensitivity. Altogether these findings show that ANKRD26 overexpression or the absence of its silencing during differentiation are responsible for myeloid blood cell abnormalities in THC2 patients.

cell biology↗