T-ALL derived bone marrow stromal stem cells promote T-ALL proliferation through the FGF2-FGFR2 pathway

doi:10.11958/20240355

Abstract

Abstract:

Objective To elucidate the mechanistic role of bone marrow mesenchymal stromal cells (BM-MSCs) in T-cell acute lymphoblastic leukemia (T-ALL), and to find effective therapeutic strategies targeting BM-MSCs.Methods A T-ALL mouse model induced by Notch-1 overexpression was constructed. An in vitro co-culture system was established to investigate the proliferative capacity of T-ALL cells upon co-culturing with leukemia-derived MSCs. RNA sequencing was performed to identify key differentially expressed genes, which were further validated by PCR. BGJ398 was injected into mice to detect tumor growth.Results Co-culturing with T-ALL-derived MSCs resulted in a significant increase in T-ALL cell proliferation. RNA sequencing results revealed that the secretion of fibroblast growth factor 2 (FGF2) from T-ALL-derived MSCs was increased, which binds to fibroblast growth factor 2 receptor (FGFR2) on T-ALL cells, activating the PI3K/AKT/mTOR signaling pathway. Blocking the interaction between FGF2 and FGFR2 using BGJ398 inhibited the growth of T-ALL tumors in mice.Conclusion BM-MSCs can promote T-ALL tumor growth through FGF2/FGFR2 pathway, and blocking FGF2/FGFR2 pathway is an effective strategy to overcome BM-MSCS-mediated T-ALL progression.

Key words: precursor cell lymphoblastic leukemia-lymphoma, fibroblast growth factor 2, cell proliferation, bone marrow mesenchymal stromal cells, BGJ398

CLC Number:

R733.71

Figures/Tables 7

References 21

[1]	ZHU H, DONG B, ZHANG Y, et al. Integrated genomic analyses identify high-risk factors and actionable targets in T-cell acute lymphoblastic leukemia[J]. Blood Sci, 2022, 4(1):16-28. doi:10.1097/BS9.0000000000000102.
[2]	COLMONE A, AMORIM M, PONTIER A L, et al. Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells[J]. Science, 2008, 322(5909):1861-1865. doi:10.1126/science.1164390.
[3]	YIN X, HU L, ZHANG Y, et al. PDGFB-expressing mesenchymal stem cells improve human hematopoietic stem cell engraftment in immunodeficient mice[J]. Bone Marrow Transplant, 2020, 55(6):1029-1040. doi:10.1038/s41409-019-0766-z.
[4]	SINGH A K, PRASAD P, CANCELAS J A. Mesenchymal stromal cells, metabolism, and mitochondrial transfer in bone marrow normal and malignant hematopoiesis[J]. Front Cell Dev Biol, 2023,11:1325291. doi:10.3389/fcell.2023.1325291.
[5]	WU C H, WENG T F, LI J P, et al. Biology and therapeutic properties of mesenchymal stem cells in leukemia[J]. Int J Mol Sci, 2024, 25(5):2527. doi:10.3390/ijms25052527.
[6]	NWABO KAMDJE A H, SEKE ETET P F, TAGNE SIMO R, et al. Emerging data supporting stromal cell therapeutic potential in cancer: reprogramming stromal cells of the tumor microenvironment for anti-cancer effects[J]. Cancer Biol Med, 2020, 17(4):828-841. doi:10.20892/j.issn.2095-3941.2020.0133.
[7]	PARK C S, YOSHIHARA H, GAO Q, et al. Stromal-induced epithelial-mesenchymal transition induces targetable drug resistance in acute lymphoblastic leukemia[J]. Cell Rep, 2023, 42(7):112804. doi:10.1016/j.celrep.2023.112804.
[8]	SøNDERGAARD R H, HøJGAARD L D, REESE-PETERSEN A L, et al. Adipose-derived stromal cells increase the formation of collagens through paracrine and juxtacrine mechanisms in a fibroblast co-culture model utilizing macromolecular crowding[J]. Stem Cell Res Ther, 2022, 13(1):250. doi:10.1186/s13287-022-02923-y.
[9]	TIAN C, ZHENG G, CAO Z, et al. Hes1 mediates the different responses of hematopoietic stem and progenitor cells to T cell leukemic environment[J]. Cell Cycle, 2013, 12(2):322-331. doi:10.4161/cc.23160.
[10]	MAJUMDAR M K, THIEDE M A, MOSCA J D, et al. Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells[J]. J Cell Physiol, 1998, 176(1):57-66. doi:10.1002/(SICI)1097-4652(199807)176:1<57::AID-JCP7>3.0.CO;2-7.
[11]	邢逸, 窦一鸣, 王敏, 等. 骨髓间充质干细胞来源外泌体对炎症微环境中巨噬细胞表型及软骨细胞的调控作用[J]. 天津医药, 2022, 50(4):343-349.
	XING Y, DOU Y M, WANG M, et al. The regulating effect of bone marrow mesenchymal stem cell-derived exosomes on macrophage phenotype and chondrocytes in the inflammatory microenvironmen[J]. Tianjin Med J, 2022, 50(4):343-349. doi:10.11958/20212366.
[12]	WANG J, LIU X, QIU Y, et al. Cell adhesion-mediated mitochondria transfer contributes to mesenchymal stem cell-induced chemoresistance on T cell acute lymphoblastic leukemia cells[J]. J Hematol Oncol, 2018, 11(1):11. doi:10.1186/s13045-018-0554-z.
[13]	CAI J, WANG J, HUANG Y, et al. ERK/Drp1-dependent mitochondrial fission is involved in the MSC-induced drug resistance of T-cell acute lymphoblastic leukemia cells[J]. Cell Death Dis, 2016, 7(11):e2459. doi:10.1038/cddis.2016.370.
[14]	JIA R, SUN T, ZHAO X, et al. DEX-induced SREBF1 promotes BMSCs differentiation into adipocytes to attract and protect residual T-cell acute lymphoblastic leukemia cells after chemotherapy[J]. Adv Sci(Weinh), 2023, 10(19):e2205854. doi:10.1002/advs.202205854.
[15]	IM J H, BUZZELLI J N, JONES K, et al. FGF2 alters macrophage polarization, tumour immunity and growth and can be targeted during radiotherapy[J]. Nat Commun, 2020, 11(1):4064. doi:10.1038/s41467-020-17914-x.
[16]	HOSAKA K, YANG Y, SEKI T, et al. Therapeutic paradigm of dual targeting VEGF and PDGF for effectively treating FGF-2 off-target tumors[J]. Nat Commun, 2020, 11(1):3704. doi:10.1038/s41467-020-17525-6.
[17]	ZHOU Z, LIU Z, OU Q, et al. Targeting FGFR in non-small cell lung cancer: implications from the landscape of clinically actionable aberrations of FGFR kinases[J]. Cancer Biol Med, 2021, 18(2):490-501. doi:10.20892/j.issn.2095-3941.2020.0120.
[18]	NEW J, ARNOLD L, ANANTH M, et al. Secretory autophagy in cancer-associated fibroblasts promotes head and neck cancer progression and offers a novel therapeutic target[J]. Cancer Res, 2017, 77(23):6679-6691. doi:10.1158/0008-5472.CAN-17-1077.
[19]	TRAER E, JAVIDI-SHARIFI N, AGARWAL A, et al. Ponatinib overcomes FGF2-mediated resistance in CML patients without kinase domain mutations[J]. Blood, 2014, 123(10):1516-1524. doi:10.1182/blood-2013-07-518381.
[20]	SHAH C A, BEI L, WANG H, et al. HoxA10 protein regulates transcription of gene encoding fibroblast growth factor 2 (FGF2) in myeloid cells[J]. J Biol Chem, 2012, 287(22):18230-18248. doi:10.1074/jbc.M111.328401.
[21]	MELNICK A F, MULLIN C, LIN K, et al. Cdc73 protects Notch-induced T-cell leukemia cells from DNA damage and mitochondrial stress[J]. Blood, 2023, 142(25):2159-2174. doi:10.1182/blood.2023020144.

基因名称	引物序列（5'→3'）	产物大小/bp
ICN1	上游：GATGGCCTCAATGGGTACAAG	74
ICN1	下游：TCGTTGTTGTTGATGTCACAGT	74
Csf2	上游：TTCAAGAAGCTAACATGTGTGC	159
Csf2	下游：GGTAACTTGTGTTTCACAGTCC	159
Fgf2	上游：AGTTGTGTCTATCAAGGGAGTG	244
Fgf2	下游：CATTGGAAGAAACAGTATGGCC	244
Igf2	上游：GTTGGTGCTTCTCATCTCTTTG	103
Igf2	下游：AAACTGAAGCGTGTCAACAAG	103
Ctf1	上游：CTCATTCCTACCCCATTTGGAG	96
Ctf1	下游：ACGTATTCCTCCAGAAGTTGTT	96
Hgf	上游：ACCTACAGGAAAACTACTGTCG	123
Hgf	下游：TGCATTCAACTTCTGAACACTG	123
Lif	上游：GCTACTATAGACGTCATGAGGG	140
Lif	下游：CAACCCAACTTTTTCCTTTGGA	140
Fgfr1	上游：GAGGACAACGTGATGAAGATCG	82
Fgfr1	下游：GGTTGGTCGTCTTCTTGTAGTA	82
Fgfr2	上游：CTAAAGGCAACCTCCGAGAATA	164
Fgfr2	下游：ACATTTTTGGGAAGCCAAGTAC	164
Fgfr3	上游：GCCTGCGTGCTAGTGTTCT	217
Fgfr3	下游：TACCATCCTTAGCCCAGACCG	217
Fgfr4	上游：TCCATGACCGTCGTACACAAT	193
Fgfr4	下游：ATTTGACAGTATTCCCGGCAG	193

基因名称	引物序列（5'→3'）	产物大小/bp
ICN1	上游：GATGGCCTCAATGGGTACAAG	74
ICN1	下游：TCGTTGTTGTTGATGTCACAGT	74
Csf2	上游：TTCAAGAAGCTAACATGTGTGC	159
Csf2	下游：GGTAACTTGTGTTTCACAGTCC	159
Fgf2	上游：AGTTGTGTCTATCAAGGGAGTG	244
Fgf2	下游：CATTGGAAGAAACAGTATGGCC	244
Igf2	上游：GTTGGTGCTTCTCATCTCTTTG	103
Igf2	下游：AAACTGAAGCGTGTCAACAAG	103
Ctf1	上游：CTCATTCCTACCCCATTTGGAG	96
Ctf1	下游：ACGTATTCCTCCAGAAGTTGTT	96
Hgf	上游：ACCTACAGGAAAACTACTGTCG	123
Hgf	下游：TGCATTCAACTTCTGAACACTG	123
Lif	上游：GCTACTATAGACGTCATGAGGG	140
Lif	下游：CAACCCAACTTTTTCCTTTGGA	140
Fgfr1	上游：GAGGACAACGTGATGAAGATCG	82
Fgfr1	下游：GGTTGGTCGTCTTCTTGTAGTA	82
Fgfr2	上游：CTAAAGGCAACCTCCGAGAATA	164
Fgfr2	下游：ACATTTTTGGGAAGCCAAGTAC	164
Fgfr3	上游：GCCTGCGTGCTAGTGTTCT	217
Fgfr3	下游：TACCATCCTTAGCCCAGACCG	217
Fgfr4	上游：TCCATGACCGTCGTACACAAT	193
Fgfr4	下游：ATTTGACAGTATTCCCGGCAG	193