Impact of the Irradiated Stromal Microenvironment on Leukemic Cell Migration: Implications for Migration Dynamics Via Cxcl12/cxcr4
Year: 2026
Type: article
Abstract: The hematopoietic microenvironment, particularly mesenchymal stromal cells (MSCs), plays a fundamental role in regulating cellular homing within the bone marrow (BM) niche through its secretome. Radiotherapy impacts not only target tumor cells but also stromal cells via the radiation-induced bystander effect (RIBE). Understanding how the secretome of radiation-exposed MSCs affects the behavior of leukemic cells is crucial for clarifying dissemination and relapse dynamics within the leukemic microenvironment. This study aims to investigate the direct effects of ionizing radiation on MSCs and evaluate the influence of MSCs modulated via RIBE on the apoptosis, gene expression, adhesion, and migratory capacity of leukemic cells in vitro. Murine cell lines of MSCs (C3H10T1/2) and leukemic lineage (C1498) were used. MSCs were subjected to different radiation doses to evaluate radioresistance, apoptosis, and DNA damage. Conditioned medium rich in the secretome of irradiated MSCs was collected, quantified for cytokines and chemokines (IL-1β, sICAM-1, and CXCL12), and applied to C1498 leukemic cells, which were then evaluated for viability, gene expression profile, adhesion, and cell migration using flow cytometry and RT-qPCR. Furthermore, the specific role of the CXCL12/CXCR4 axis was validated using the CXCR4 antagonist AMD3100. MSCs exhibited radioresistance up to doses of 4Gy, presenting significant damage and apoptosis only at a 6Gy dose. Irradiated MSCs secreted elevated levels of IL-1β, sICAM-1, and the chemokine CXCL12. Exposure of leukemic cells to the secretome of irradiated MSCs did not alter cell viability or the expression of migration-associated genes. However, a significant increase in the migration rate of C1498 leukemic cells was observed, induced by the CXCL12-rich secretome. Blocking the CXCR4 with the inhibitor AMD3100 reversed the migratory stimulus, confirming the dependence on the CXCL12/CXCR4 axis for the regulation of leukemic trafficking. The findings indicate that RIBE mediated by irradiated MSCs functionally alters the microenvironment. Increased secretion of CXCL12 by radiation-exposed MSCs acts as an essential chemotactic factor that stimulates the transit of leukemic blasts. This mechanism suggests that radiotherapy can modulate the dynamics of the BM niche, promoting a favorable environment for CXCL12/CXCR4-dependent homing or tumor dissemination. Mesenchymal stromal cells RIBE promotes increased leukemic cell migration in vitro. Therapeutic targeting of this axis emerges as a potential strategy to mitigate adverse effects in the stromal microenvironment during or after radiotherapeutic regimens in hematological malignancies, aiming to exploit its cellular and molecular therapeutic potential in hematopoietic stem cell transplantation contexts as well. This study was conducted with the support of the Coordination for the Improvement of Higher Education Personnel – Brazil (CAPES) – Finance Code 88887.688784/2022-00.
Institution: Universidade de São Paulo
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7223152220