Abstract
The development of acute lymphoblastic leuakemia (ALL) is partly attributed to the protection effects of abnormal bone marrow (BM) microenvironment, especially mesenchymal stromal cells (MSCs), which interact bilaterally with leukaemia cells, leading to ALL progression. In order to investigate MSCs-based microenvironment targeted therapeutic strategies, Notch1-induced T-cell ALL (T-ALL) mice models were used and dynamic alterations of BM-MSCs with increased cell viability during T-ALL development was observed. In T-ALL mice derived stroma-based condition, leukaemia cells showed significantly elevated growth capacity indicating that MSCs participated in leukemic niche formation. RNA sequence results revealed that T-ALL derived MSCs secreted fibroblast growth factor 2 (FGF2), which combined with fibroblast growth factor receptor 2 (FGFR2) on leukaemia cells, resulting in activation of PI3K/AKT/mTOR signalling in leukaemia cells. In vitro blocking the interaction between FGF2 and FGFR2 with infigratinib (BGJ398), a FGFR1-3 kinase inhibitor, or knockdown FGF2 expression in MSCs in co-culture system, both induced deactivation of PI3K/AKT/mTOR signalling pathway in T-ALL cells and dysregulations of genes associated with cell cycle and apoptosis, leading to decrease of leukaemia cells. In mouse model with FGF2 and FGFR2 blockade, overall survival was extended and dissemination of leukaemia cells in BM, spleen, liver and peripheral blood was decreased. After subcutaneous injection of primary human T-ALL cells with MSCs, tumour growth was suppressed when FGF2/FGFR2 was interrupted. Thus, inhibition of FGF2/FGFR2 interaction appears to be a valid strategy to overcome BM-MSCs mediated progression of T-ALL, and infigratinib could indeed improve outcomes in T-ALL, which provide theoretical basis of infigratinib as a therapeutic strategy to control disease progression.
Disclosures
No relevant conflicts of interest to declare.
Author notes
*Asterisk with author names denotes non-ASH members.
