Comprehensive analysis of mesenchymal cells reveals a dysregulated TGF-β/Wnt/HOXB7 axis in patients with myelofibrosis.

Autor: Ganesan S; Institut de Recherche Saint-Louis, INSERM UMRS 1131, Université Paris Cité, Paris, France., Awan-Toor S; Institut de Recherche Saint-Louis, INSERM UMRS 1131, Université Paris Cité, Paris, France., Guidez F; Institut de Recherche Saint-Louis, INSERM UMRS 1131, Université Paris Cité, Paris, France., Maslah N; Institut de Recherche Saint-Louis, INSERM UMRS 1131, Université Paris Cité, Paris, France., Rahimy R; Laboratoire de recherche en génétique et hématologie translationnelle, Institut Gonçalo Moniz, Salvador, Brazil., Aoun C; Institut de Recherche Saint-Louis, INSERM UMRS 1131, Université Paris Cité, Paris, France., Gou P; Institut de Recherche Saint-Louis, INSERM UMRS 1131, Université Paris Cité, Paris, France., Guiguen C; Institut de Recherche Saint-Louis, INSERM UMRS 1131, Université Paris Cité, Paris, France., Soret J; Centre d'Investigations Cliniques, INSERM CIC 1427, Université Paris Cité, AP-HP, Hôpital Saint-Louis, Paris, France., Ravdan O; Service de Biologie Cellulaire, AP-HP, Hôpital Saint-Louis, Paris, France., Bisio V; INSERM U1160, Institut de Recherche Saint-Louis, Université Paris-Cité, Paris, France., Dulphy N; INSERM U1160, Institut de Recherche Saint-Louis, Université Paris-Cité, Paris, France., Lobry C; Institut de Recherche Saint Louis, INSERM U944, CNRS UMR7212, Université Paris-Cité, Paris, France., Schlageter MH; Service de Biologie Cellulaire, AP-HP, Hôpital Saint-Louis, Paris, France., Souyri M; Institut de Recherche Saint-Louis, INSERM UMRS 1131, Université Paris Cité, Paris, France., Giraudier S; Institut de Recherche Saint-Louis, INSERM UMRS 1131, Université Paris Cité, Paris, France., Kiladjian JJ; Institut de Recherche Saint-Louis, INSERM UMRS 1131, Université Paris Cité, Paris, France., Chomienne C; Institut de Recherche Saint-Louis, INSERM UMRS 1131, Université Paris Cité, Paris, France., Cassinat B; Institut de Recherche Saint-Louis, INSERM UMRS 1131, Université Paris Cité, Paris, France.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2024 Oct 29. Date of Electronic Publication: 2024 Oct 29.
DOI: 10.1172/jci.insight.173665
Abstrakt: Despite the advances in the understanding and treatment of myeloproliferative neoplasm (MPN), the disease remains incurable with the risk of evolution to AML or myelofibrosis (MF). Unfortunately, the evolution of the disease to MF remains still poorly understood impeding preventive and therapeutic options. Recent studies in solid tumor microenvironment and organ fibrosis have shed instrumental insights on their respective pathogenesis and drug resistance, yet such precise data are lacking in MPN. In this study, through a patient-sample driven transcriptomic and epigenetic description of the MF microenvironment landscape and cell-based analyses, we identify HOXB7 overexpression and more precisely a novel TGFβ-Wnt-HOXB7 pathway as associated to a pro-fibrotic and pro-osteoblastic biased differentiation of mesenchymal stromal cells (MSCs). Using gene-based and chemical inhibition of this pathway we reverse the abnormal phenotype of MSCs from myelofibrosis patients, providing the MPN field with a potential novel target to prevent and manage evolution to MF.
Databáze: MEDLINE