Blockade of FGF2/FGFR2 partially overcomes bone marrow mesenchymal stromal cells mediated progression of T-cell acute lymphoblastic leukaemia

• Published in: Cell death & disease 2022-11, Vol.13 (11), p.922-922, Article 922
• Main Authors: Tian, Chen, Li, Yueyang, Wang, Lina, Si, Junqi, Zheng, Yaxin, Kang, Junnan, Wang, Yafei, You, M. James, Zheng, Guoguang
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 38/109; 38/77; 38/91; 631/67/327; 692/699/1541/1990/283/2125; Acute lymphoblastic leukemia; AKT protein; Animal models; Animals; Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; Bone marrow; Bone Marrow - metabolism; Bone Marrow Cells - metabolism; Cell activation; Cell Biology; Cell Culture; Cell cycle; Cell viability; Deactivation; Enzyme inhibitors; Fibroblast growth factor 2; Fibroblast Growth Factor 2 - metabolism; Fibroblast Growth Factor 2 - pharmacology; Fibroblast growth factor receptor 1; Fibroblast growth factor receptor 2; Fibroblasts; Growth factors; Humans; Immunology; Leukemia; Life Sciences; Lymphocytes T; Mesenchymal stem cells; Mesenchymal Stem Cells - metabolism; Mesenchyme; Mice; Microenvironments; Notch1 protein; Nucleotide sequence; Peripheral blood; Phosphatidylinositol 3-Kinases - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Proto-Oncogene Proteins c-akt - metabolism; Receptor, Fibroblast Growth Factor, Type 2 - genetics; Receptor, Fibroblast Growth Factor, Type 2 - metabolism; Signal transduction; Stromal cells; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tumor Microenvironment; Tumors
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-05377-5

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.