PMID- 36333298
OWN - NLM
STAT- MEDLINE
DCOM- 20221108
LR  - 20230121
IS  - 2041-4889 (Electronic)
VI  - 13
IP  - 11
DP  - 2022 Nov 4
TI  - Blockade of FGF2/FGFR2 partially overcomes bone marrow mesenchymal stromal cells 
      mediated progression of T-cell acute lymphoblastic leukaemia.
PG  - 922
LID - 10.1038/s41419-022-05377-5 [doi]
LID - 922
AB  - 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.
CI  - (c) 2022. The Author(s).
FAU - Tian, Chen
AU  - Tian C
AUID- ORCID: 0000-0002-0995-990X
AD  - Department of hematology, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 
      300060, China. tianchen@tjmuch.com.
FAU - Li, Yueyang
AU  - Li Y
AUID- ORCID: 0000-0003-4356-9451
AD  - Department of hematology, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 
      300060, China.
AD  - State Key Laboratory of Experimental Hematology, National Clinical Research 
      Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of 
      Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and 
      Peking Union Medical College, Tianjin, 300020, China.
FAU - Wang, Lina
AU  - Wang L
AD  - State Key Laboratory of Experimental Hematology, National Clinical Research 
      Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of 
      Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and 
      Peking Union Medical College, Tianjin, 300020, China.
FAU - Si, Junqi
AU  - Si J
AD  - Department of hematology, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 
      300060, China.
FAU - Zheng, Yaxin
AU  - Zheng Y
AD  - Department of hematology, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 
      300060, China.
FAU - Kang, Junnan
AU  - Kang J
AD  - Department of hematology, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 
      300060, China.
AD  - State Key Laboratory of Experimental Hematology, National Clinical Research 
      Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of 
      Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and 
      Peking Union Medical College, Tianjin, 300020, China.
FAU - Wang, Yafei
AU  - Wang Y
AD  - Department of hematology, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 
      300060, China.
FAU - You, M James
AU  - You MJ
AD  - Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, 77479, USA.
FAU - Zheng, Guoguang
AU  - Zheng G
AUID- ORCID: 0000-0002-0829-3501
AD  - State Key Laboratory of Experimental Hematology, National Clinical Research 
      Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of 
      Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and 
      Peking Union Medical College, Tianjin, 300020, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221104
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - A4055ME1VK (infigratinib)
RN  - 103107-01-3 (Fibroblast Growth Factor 2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.10.1 (FGFR2 protein, human)
SB  - IM
MH  - Humans
MH  - Mice
MH  - Animals
MH  - Fibroblast Growth Factor 2/pharmacology/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - *Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology
MH  - Receptor, Fibroblast Growth Factor, Type 2/genetics/metabolism
MH  - Bone Marrow/metabolism
MH  - *Mesenchymal Stem Cells/metabolism
MH  - Bone Marrow Cells/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Tumor Microenvironment
PMC - PMC9636388
COIS- The authors declare no competing interests.
EDAT- 2022/11/06 06:00
MHDA- 2022/11/09 06:00
PMCR- 2022/11/04
CRDT- 2022/11/05 00:16
PHST- 2022/02/28 00:00 [received]
PHST- 2022/10/26 00:00 [accepted]
PHST- 2022/10/19 00:00 [revised]
PHST- 2022/11/06 06:00 [pubmed]
PHST- 2022/11/09 06:00 [medline]
PHST- 2022/11/05 00:16 [entrez]
PHST- 2022/11/04 00:00 [pmc-release]
AID - 10.1038/s41419-022-05377-5 [pii]
AID - 5377 [pii]
AID - 10.1038/s41419-022-05377-5 [doi]
PST - epublish
SO  - Cell Death Dis. 2022 Nov 4;13(11):922. doi: 10.1038/s41419-022-05377-5.