Int J Cancer. 2025 Apr 26. doi: 10.1002/ijc.35418. Online ahead of print.
ABSTRACT
Relapse and disease progression are the primary causes of treatment failure and subsequent mortality in children with B-cell acute lymphocytic leukemia (B-ALL). At diagnosis and during treatment, dyslipidemia and the bone marrow adipose microenvironment are commonly observed in pediatric leukemia. However, the intricate connection between these factors and disease progression remains largely unexplored. We found that abnormal triglyceride accumulation increased the risk of death. Further investigation into the adipogenic potential of BM-MSCs revealed a correlation between higher adipogenicity and elevated serum TG levels, which subsequently led to the rapid proliferation of leukemia cells and heightened the risk of post-relapse mortality. Through RNA sequencing, Gremlin1 (GREM1) was identified as an important factor affecting adipogenicity. Silencing of GREM1 in BM-MSCs induced adipogenic differentiation, partly through the BMP/SMAD signaling pathway. In an in vitro co-culture model, shGREM1-MSCs promoted B-ALL cell proliferation and induced drug resistance to dexamethasone, while increasing sensitivity to L-asparaginase. Furthermore, GREM1-deficient BM-MSCs promoted B-ALL disease progression in xenograft models. This study provides new insights into overcoming drug resistance, relapse, and death by elucidating the novel mechanism by which GREM1 deficiency induces adipogenic differentiation of BM-MSCs and promotes B-ALL disease progression.
PMID:40285538 | DOI:10.1002/ijc.35418
