Gas6/AXL Signaling Regulates Self-Renewal of Chronic Myelogenous Leukemia Stem Cells by Stabilizing β-Catenin

Jin, Yanli; Nie, Danian; Li, Juan; Du, Xin; Lu, Yuhong; Li, Yangqiu; Liu, Chang; Zhou, Jingfeng; Pan, Jingxuan

doi:10.1158/1078-0432.ccr-16-1298

Cited by 39 publications

(40 citation statements)

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“…The AXL‐dependent epirubicin resistance mediated by c‐MYC is likely achieved through regulation of the stemness of a subset of self‐renewing EAC stem cells. Our findings are consistent with the recent report showing that Gas6/AXL signaling stabilizes β‐catenin protein in an AKT‐dependent mechanism, thereby regulating self‐renewal of drug‐resistant leukemia stem cells (Jin et al ., ). We confirmed that pharmacologic inhibition of AXL by R428 is sufficient to down‐regulate c‐MYC expression and overcome epirubicin resistance in EAC cells.…”

Section: Discussionmentioning

confidence: 97%

Transcriptional upregulation of c‐MYC by AXL confers epirubicin resistance in esophageal adenocarcinoma

2018

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AXL receptor tyrosine kinase is overexpressed in esophageal adenocarcinoma (EAC) and several other types of malignancies; hence, it may be a valuable therapeutic target. Herein, we investigated the role of AXL in regulating c‐MYC expression and resistance to the chemotherapeutic agent epirubicin in EAC. Using in vitro EAC cell models, we found that AXL overexpression enhances epirubicin resistance in sensitive cells. Conversely, genetic knockdown or pharmacological inhibition of AXL sensitizes resistant cells to epirubicin. Notably, we showed that inhibition or knockdown of c‐MYC markedly sensitizes AXL‐dependent resistant cells to epirubicin, and our data demonstrated that AXL promotes epirubicin resistance through transcriptional upregulation of c‐MYC. We showed that AXL overexpression significantly increased transcriptional activity, mRNA, and protein levels of c‐MYC. Conversely, AXL knockdown reversed these effects. Mechanistic investigations indicated that AXL upregulates c‐MYC expression through activation of the AKT/β‐catenin signaling pathway. Data from a tumor xenograft mouse model indicated that inhibition of AXL with R428 in combination with epirubicin synergistically suppresses tumor growth and proliferation. Our results demonstrate that AXL promotes epirubicin resistance through transcriptional upregulation of c‐MYC in EAC. Our findings support future clinical trials to assess the therapeutic potential of R428 in epirubicin‐resistant tumors with overexpression of AXL and activation of c‐MYC.

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Section: Discussionmentioning

confidence: 97%

Transcriptional upregulation of c‐MYC by AXL confers epirubicin resistance in esophageal adenocarcinoma

2018

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“…Axl, a member of the receptor tyrosine kinase family and a prognostic marker in AML, induces the expression of its ligand Gas6 (growth arrest-specific gene 6) from the BMM and increases the proliferation of leukemic cells (Janning et al, 2015). The same axis has been reported to regulate the self-renewal of CML cells (Jin et al, 2017). Additionally, secreted vesicles, called exosomes or microvesicles, are emerging factors in the evolution and progression of different cancer types, including leukemia (Krause and Scadden, 2015) (see poster and Box 2).…”

Section: Cytokines Chemokines and Secreted Vesicles In The Extracellmentioning

confidence: 98%

The bone marrow microenvironment in health and disease at a glance

Kumar

Godavarthy

Krause

2018

Journal of Cell Science

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The bone marrow microenvironment (BMM) is the 'domicile' of hematopoietic stem cells, as well as of malignant processes that can develop there. Multiple and complex interactions with the BMM influence hematopoietic stem cell (HSC) physiology, but also the pathophysiology of hematological malignancies. Reciprocally, hematological malignancies alter the BMM, in order to render it more hospitable for malignant progression. In this Cell Science at a Glance article and accompanying poster, we highlight concepts of the normal and malignant hematopoietic stem cell niches. We present the intricacies of the BMM in malignancy and provide approaches for targeting the interactions between malignant cells and their BMM. This is done in an effort to augment existing treatment strategies in the future.

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“…Peripheral blood (PB) or bone marrow (BM) samples were obtained from patients with CML (Supplementary Table S1) and from healthy adult donors in the First Affiliated Hospital of Jinan University, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen Memorial Hospital, and Guangdong Provincial People's Hospital after informed consent according to the institutional guidelines and the Declaration of Helsinki principles. The primary human CD34 þ cells were sorted by using a MACS bead kit (Miltenyi Biotec) as described previously (8,14,17).…”

Section: Cell Lines and Primary Leukemia Cellsmentioning

confidence: 99%

“…The maintenance of LSCs is independent of BCR-ABL kinase activity (11), but regulated by multiple signaling pathways including the developmental signaling pathways (e.g., Wnt/b-catenin, Notch, Hedgehog), epigenetic regulators (e.g., SIRT1, PRMT5, EZH2), transcriptional factors (e.g., p53, NF-kB, FOXM1), cell metabolism regulators (e.g., Slc15A2, Alox5), and other cell regulators (e.g., PPARg, Gas6/AXL, IL1RAP, PTEN; refs. [12][13][14][15][16][17][18][19][20]. However, the signaling pathways that are responsible for LSC maintenance remain to be fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

PTEN Is Fundamental for Elimination of Leukemia Stem Cells Mediated by GSK126 Targeting EZH2 in Chronic Myelogenous Leukemia

Zhou

Nie

et al. 2018

Clinical Cancer Research

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Leukemia stem cells (LSCs) are an important source of tyrosine kinase inhibitor resistance and disease relapse in patients with chronic myelogenous leukemia (CML). Targeting LSCs may be an attractive strategy to override this thorny problem. Given that was overexpressed in primary CML CD34 cells, our purpose in this study was to evaluate the effects of targeting EZH2 on CML LSCs and clarify its underlying mechanism. Human primary CML CD34 cells and retrovirally -driven CML mouse models were employed to evaluate the effects of suppression of EZH2 by- or -specific shRNA and Recruitment of EZH2 and H3K27me3 on the promoter of tumor-suppressor gene in CML cells was measured by chromatin immunoprecipitation assay. Our results showed that pharmacologic inhibition of EZH2 by GSK126 not only elicited apoptosis and restricted cell growth in CML bulk leukemia cells, but also decreased LSCs in CML CD34 cells while sparing those from normal bone marrow CD34 cells. Suppression of EZH2 by GSK126 or specific shRNA prolonged survival of CML mice and reduced the number of LSCs in mice. knockdown resulted in elevation of and led to impaired recruitment of EZH2 and H3K27me3 on the promoter of gene. The effect of knockdown in the CML mice was at least partially reversed by knockdown. These findings improve the understanding of the epigenetic regulation of stemness in CML LSCs and warrant clinical trial of GSK126 in refractory patients with CML. .

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Gas6/AXL Signaling Regulates Self-Renewal of Chronic Myelogenous Leukemia Stem Cells by Stabilizing β-Catenin

Cited by 39 publications

References 50 publications

Transcriptional upregulation of c‐MYC by AXL confers epirubicin resistance in esophageal adenocarcinoma

Transcriptional upregulation of c‐MYC by AXL confers epirubicin resistance in esophageal adenocarcinoma

The bone marrow microenvironment in health and disease at a glance

PTEN Is Fundamental for Elimination of Leukemia Stem Cells Mediated by GSK126 Targeting EZH2 in Chronic Myelogenous Leukemia

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