CXCR4 Inhibition Enhances Efficacy of FLT3 Inhibitors in FLT3-Mutated AML Augmented by Suppressed TGF-β Signaling

Kim, Bo-Reum; Jung, Seung‐Hyun; Han, A-Reum; Park, Gyeong Sin; Kim, Hee-Je; Yuan, Bin; Battula, Venkata Lokesh; Andreeff, Michael; Konopleva, Marina; Chung, Yeun‐Jun; Cho, Byung-Sik

doi:10.3390/cancers12071737

Cited by 11 publications

(9 citation statements)

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“…For example, FLT3-ITD mutation upregulates the expression levels of STAT5 (a regulatory factor for CXCR4 mRNA level), causing an increase in CXCR4 expression on the cell surface in AML ( Cao et al, 2019b ). Besides, LY2510924, a CXCR4 inhibition, could significantly increase the effect of FLT3 inhibitors in the AML cells with FLT3-ITD mutation ( Kim et al, 2020 ). Identifying the common downstream cellular mechanisms of FLT3-ITD and CXCR4-CXCL12 axis helps to further understand the interactions between them from another aspect.…”

Section: Discussionmentioning

confidence: 99%

“…The signal pathways activated by the CXCL12/CXCR4 axis have been demonstrated to show effects in interactions between tumor cells and the microenvironment in AML, and the interactions would cause chemoresistance and AML relapse ( Lee et al, 2017 ; Cao et al, 2019b ). Several recent publications suggest an interaction between FLT3-ITD mutation and CXCL12/CXCR4 axis, and the CXCL12/CXCR4 axis has been proved an important role in the rapid emergence of resistance to FLT3 inhibitors ( Cao et al, 2019b ; Kim et al, 2020 ; Waldeck et al, 2020 ). Although it has been identified that the combination of the FLT3 inhibitor and CXCR4 antagonist could improve the sensitivity of chemotherapy treatment in AML cells ( Jacobi et al, 2010 ; Kim et al, 2020 ), the lack of understanding of the impact on AML cells produced by the interaction between FLT3-ITD mutation and the CXCL12/CXCR4 axis restricts the development of the related research.…”

Section: Introductionmentioning

confidence: 99%

“…Several recent publications suggest an interaction between FLT3-ITD mutation and CXCL12/CXCR4 axis, and the CXCL12/CXCR4 axis has been proved an important role in the rapid emergence of resistance to FLT3 inhibitors ( Cao et al, 2019b ; Kim et al, 2020 ; Waldeck et al, 2020 ). Although it has been identified that the combination of the FLT3 inhibitor and CXCR4 antagonist could improve the sensitivity of chemotherapy treatment in AML cells ( Jacobi et al, 2010 ; Kim et al, 2020 ), the lack of understanding of the impact on AML cells produced by the interaction between FLT3-ITD mutation and the CXCL12/CXCR4 axis restricts the development of the related research. Therefore, it is important to identify the downstream signaling events as a result of the interaction.…”

Section: Introductionmentioning

confidence: 99%

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Dysregulation of miR-138-5p/RPS6KA1-AP2M1 Is Associated With Poor Prognosis in AML

Chen

et al. 2021

Front. Cell Dev. Biol.

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Acute myeloid leukemia (AML) is a malignant disease of hematopoietic stem/progenitor cells, and most AML patients are in a severe state. Internal tandem duplication mutations in FLT3 gene (FLT3-ITD) detected in AML stem cells account for 20–30 percent of AML patients. In this study, we attempted to study the impact of the interaction of FLT3-ITD mutation and the CXCL12/CXCR4 axis in AML, and the possible mechanisms caused by the impact by bioinformatics. Gene set variation analysis (GSVA) revealed that the PI3K-Akt-mTOR pathway positively correlated with the status of FLT3-ITD mutation. Multiple survival analyses were performed on TCGA-AML to screen the prognostic-related genes, and RPS6KA1 and AP2M1 are powerful prognostic candidates for overall survival in AML. WGCNA, KEGG/GO analysis, and the functional roles of RPS6KA1 and AP2M1 in AML were clarified by correlation analysis. We found that the expression levels of RPS6KA1 and AP2M1 were significantly associated with chemoresistance of AML, and the CXCL12/CXCR4 axis would regulate RPS6KA1/AP2M1 expression. Besides, miR-138-5p, regulated by the CXCL12/CXCR4 axis, was the common miRNA target of RPS6KA1 and AP2M1. Taken together, the interaction of FLT3-ITD mutation and the CXCL12/CXCR4 axis activated the PI3K-Akt-mTOR pathway, and the increased expression of RPS6KA1 and AP2M1 caused by hsa-miR-138-5p downregulation regulates the multi-resistance gene expression leading to drug indications.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dysregulation of miR-138-5p/RPS6KA1-AP2M1 Is Associated With Poor Prognosis in AML

Chen

et al. 2021

Front. Cell Dev. Biol.

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“…TGF-β expression is upregulated in stromal cells in the AML-BME and contributes to tumor growth and treatment resistance. Silencing of TGF-β in stromal cells co-cultured with FLT3-ITD-AML enhances treatment-induced AML apoptosis and sensitizes AML cells to combination chemotherapy [ 32 ]. Moreover, TGF-β inhibition by small-molecule inhibitors or neutralizing antibodies is a strategy that has been explored to counteract chemotherapy resistance in several malignancies, including AML [ 5 ].…”

Section: Discussionmentioning

confidence: 99%

Bone marrow stromal cells induce an ALDH+ stem cell-like phenotype and enhance therapy resistance in AML through a TGF-β-p38-ALDH2 pathway

Yuan

Dana

et al. 2020

PLoS ONE

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The bone marrow microenvironment (BME) in acute myeloid leukemia (AML) consists of various cell types that support the growth of AML cells and protect them from chemotherapy. Mesenchymal stromal cells (MSCs) in the BME have been shown to contribute immensely to leukemogenesis and chemotherapy resistance in AML cells. However, the mechanism of stroma-induced chemotherapy resistance is not known. Here, we hypothesized that stromal cells promote a stem-like phenotype in AML cells, thereby inducing tumorigenecity and therapy resistance. To test our hypothesis, we co-cultured AML cell lines and patient samples with BM-derived MSCs and determined aldehyde dehydrogenase (ALDH) activity and performed gene expression profiling by RNA sequencing. We found that the percentage of ALDH+ cells increased dramatically when AML cells were co-cultured with MSCs. However, among the 19 ALDH isoforms, ALDH2 and ALDH1L2 were the only two that were significantly upregulated in AML cells co-cultured with stromal cells compared to cells cultured alone. Mechanistic studies revealed that the transforming growth factor-β1 (TGF-β1)-regulated gene signature is activated in AML cells co-cultured with MSCs. Knockdown of TGF-β1 in BM-MSCs inhibited stroma-induced ALDH activity and ALDH2 expression in AML cells, whereas treatment with recombinant TGF-β1 induced the ALDH+ phenotype in AML cells. We also found that TGF-β1-induced ALDH2 expression in AML cells is mediated by the non-canonical pathway through the activation of p38. Interestingly, inhibition of ALDH2 with diadzin and CVT-10216 significantly inhibited MSC-induced ALDH activity in AML cells and sensitized them to chemotherapy, even in the presence of MSCs. Collectively, BM stroma induces ALDH2 activity in AML cells through the non-canonical TGF-β pathway. Inhibition of ALDH2 sensitizes AML cells to chemotherapy.

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“…Monodrug therapy with LY2510924 demonstrated dose-dependent antitumor growth and anti-metastasis activities in leukemia, multiple solid tumor xenograft models, and a breast cancer metastatic model. When used in combination, it increased the efficiency of FLT3 inhibitors in preclinical FLT3-mutated AML models by suppressing TGF-β signaling ( 102 ). Secondly, the feature and advantage of LY2510924 is its high in vivo stability.…”

Section: Macrocyclic Peptides Targeting Extracellular Ppismentioning

confidence: 99%

Utilization of macrocyclic peptides to target protein-protein interactions in cancer

Yang

Zhu

et al. 2022

Front. Oncol.

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Protein-protein interactions (PPIs) play vital roles in normal cellular processes. Dysregulated PPIs are involved in the process of various diseases, including cancer. Thus, these PPIs may serve as potential therapeutic targets in cancer treatment. However, despite rapid advances in small-molecule drugs and biologics, it is still hard to target PPIs, especially for those intracellular PPIs. Macrocyclic peptides have gained growing attention for their therapeutic properties in targeting dysregulated PPIs. Macrocyclic peptides have some unique features, such as moderate sizes, high selectivity, and high binding affinities, which make them good drug candidates. In addition, some oncology macrocyclic peptide drugs have been approved by the US Food and Drug Administration (FDA) for clinical use. Here, we reviewed the recent development of macrocyclic peptides in cancer treatment. The opportunities and challenges were also discussed to inspire new perspectives.

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CXCR4 Inhibition Enhances Efficacy of FLT3 Inhibitors in FLT3-Mutated AML Augmented by Suppressed TGF-β Signaling

Cited by 11 publications

References 50 publications

Dysregulation of miR-138-5p/RPS6KA1-AP2M1 Is Associated With Poor Prognosis in AML

Dysregulation of miR-138-5p/RPS6KA1-AP2M1 Is Associated With Poor Prognosis in AML

Bone marrow stromal cells induce an ALDH+ stem cell-like phenotype and enhance therapy resistance in AML through a TGF-β-p38-ALDH2 pathway

Utilization of macrocyclic peptides to target protein-protein interactions in cancer

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