IFNγ Drives Long-Term Bone Marrow Niche Dysfunction Following Doxorubicin-Based Chemotherapy
Abstract
Cancer survivors experience long-term skeletal and hematopoietic complications that limit quality of life following chemotherapy (CTX), yet the mechanisms underlying these defects remain incompletely understood. Using a murine model of doxorubicin (DOX)-based leukemia induction therapy, we show that CTX induces inflammatory remodeling of the bone marrow (BM) niche. DOX treatment resulted in loss of arteriolar vasculature, blockade of mesenchymal stromal cell (MSC) differentiation, trabecular bone loss, and reduced niche capacity to maintain hematopoietic stem cells (HSCs). These defects were accompanied by aberrant immune activation within the BM, marked by increased interferon-γ (IFNγ) production by CD8⁺ T cells. Inhibition of IFNγ signaling partially restored arteriolar vessels and adipogenic differentiation. Moreover, combined IFNγ blockade and deferoxamine mesylate (DFM), which promotes vascular recovery, attenuated chemotherapy-associated skeletal damage. Consistent with these findings, paired BM samples collected at diagnosis and post-CTX from leukemia patients exhibited altered MSC lineage priming, upregulation of inflammatory pathways, and expansion of BM CD8⁺ memory T cells after treatment. Together, these findings implicate IFNγ-driven chronic inflammatory remodeling as a central mechanism of CTX-associated BM niche dysfunction and pinpoints inflammatory signaling as a potential target to preserve BM function and long-term tissue integrity.
Article Details
Authors (38)
Ximing Li
Alicia G .Aguilar-Navarro
Princess Margaret Cancer Center, Toronto, Ontario, Canada
Mursal Nader
University of Toronto, Toronto, Ontario, Canada
Soheil Jahangiri
Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Ho Seok Lee
Gibran Edun
Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Mark Gower
Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Dustin Yang
University of Toronto, Toronto, Ontario, Canada
Minerva Fernandez
Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Brian Lin
Donghun Oh
Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Stephanie Farhat
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
David-Michael Phillips
Sunnybrook Research Institute, Toronto, Ontario, Canada
Samantha Bartman
University of Toronto, Toronto, Ontario, Canada
David Iain Murray
Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada
Christina Marie Kaszuba
University of Rochester Medical Center, Rochester, New York, United States
Pathum Kossinna
Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Manjula Kamath
University of Toronto, Toronto, Ontario, Canada
Cari Whyne
Sunnybrook Research Institute, Toronto, Ontario, Canada
Gregory Schwartz
University of Colorado School of Medicine, Aurora, Colorado, United States
Jeevisha Bajaj
Thomas Kislinger
Bo O. Zhou
Daniel L Coutu
Ottawa Hospital Research Institute, Canada
Margarete K Akens
Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Adele Changoor
Lunenfeld Tanenbaum Research Institute, Toronto, Ontario, Canada
Thierry Mallevaey
University of Toronto, Toronto, Ontario, Canada
Federico Gaiti
Courtney L Jones
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
Shruti Naik
Mark D Minden
Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Andrea Arruda
Princess Margaret Cancer Centre, University Health Network
Johann K. Hitzler
The Hospital for Sick Children, Toronto, Ontario, Canada
Ki Jun Lee
USC, Los Angeles, California, United States
Yong-mi Kim
Ralf H Adams
Max-Planck-Institute for Molecular Biomedicine, Muenster, Germany
Kishor K. Sivaraj
Max Planck Institute for Molecular Biomedicine, Münster, Germany
Anastasia N Tikhonova
Princess Margaret Cancer Centre, Toronto, Ontario, Canada