Blockade of FGF2/FGFR2 Partially Overcomes Bone Marrow Mesenchymal Stromal Cells Mediated Progression of T-cell Acute Lymphoblastic Leukaemia

Authors

Chen Tian
Yueyang Li
Lina Wang
Junqi Si
Yaxin Zheng
Junnan Kang
Yafei Wang
M James You
Guoguang Zheng

Publication Date

11-4-2022

Journal

Cell Death & Disease

Abstract

The development of acute lymphoblastic leuakemia (ALL) is partly attributed to the effects of bone marrow (BM) microenvironment, especially mesenchymal stromal cells (MSCs), which interact bilaterally with leukaemia cells, leading to ALL progression. In order to find 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 leukaemic 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 pathway in leukaemia cells. In vitro blocking the interaction between FGF2 and FGFR2 with BGJ398 (infigratinib), a FGFR1-3 kinase inhibitor, or knockdown FGF2 in MSCs by interference caused deactivation of PI3K/AKT/mTOR pathway and dysregulations of genes associated with cell cycle and apoptosis in ALL cells, leading to decrease of leukaemia cells. In mouse model received BGJ398, 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 BGJ398 could indeed improve outcomes in T-ALL, which provide theoretical basis of BGJ398 as a BM microenvironment based therapeutic strategy to control disease progression.

Keywords

Humans, Mice, Animals, Fibroblast Growth Factor 2, Proto-Oncogene Proteins c-akt, Phosphatidylinositol 3-Kinases, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Receptor, Fibroblast Growth Factor, Type 2, Bone Marrow, Mesenchymal Stem Cells, Bone Marrow Cells, TOR Serine-Threonine Kinases, Tumor Microenvironment, Cancer microenvironment, Acute lymphocytic leukaemia

Comments

Associated Data

DOI

10.1038/s41419-022-05377-5

PMID

36333298

PMCID

PMC9636388

PubMedCentral® Posted Date

November 2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes