Integrin alphavbeta3 enhances β-catenin signaling in acute myeloid leukemia harboring Fms-like tyrosine kinase-3 internal tandem duplication mutations: implications for microenvironment influence on sorafenib sensitivity

Yi, Hai; Zeng, Dongfeng; Shen, Zhaohua; Liu, Jun; Wang, Xiaoguo; Liu, Yao; Zhang, Xi; Kong, Peiyan

doi:10.18632/oncotarget.9617

Cited by 46 publications

(51 citation statements)

References 30 publications

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“…Moreover, different in vivo studies have identified β3 integrin as an integral part of leukemogenesis in AML, although it is dispensable for normal hematopoiesis (Miller et al, 2013). Integrin β3 was recently shown to enhance Wnt signaling in AML cells by mediating resistance to the kinase inhibitor sorafenib (Yi et al, 2016). In addition, the integrin-binding glycoprotein CD98 was shown to promote AML proliferation and maintenance of leukemic stem cells through an increased engagement with the BMM, while anti-CD98 blockade inhibited AML growth (Bajaj et al, 2016).…”

Section: Cell Adhesion Molecules and Other Niche Components Involved mentioning

confidence: 99%

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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Section: Cell Adhesion Molecules and Other Niche Components Involved mentioning

confidence: 99%

The bone marrow microenvironment in health and disease at a glance

Kumar

Godavarthy

Krause

2018

Journal of Cell Science

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“…30 Active b-catenin was up-regulated in stroma-adherent cells, suggesting a role in AML-stromal interaction through direct binding, and of note integrin avb3 has been implicated in modulating sensitivity to sorafenib. 31 This observation was absent in adhesion to NBM-derived MSCs, suggesting a therapeutic window for the malignant versus healthy BM niche.…”

Section: Discussionmentioning

confidence: 96%

Combination of a mitogen‐activated protein kinase inhibitor with the tyrosine kinase inhibitor pacritinib combats cell adhesion‐based residual disease and prevents re‐expansion of FLT3‐ITD acute myeloid leukaemia

et al. 2020

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Minimal residual disease (MRD) in acute myeloid leukaemia (AML) poses a major challenge due to drug insensitivity and high risk of relapse. Intensification of chemotherapy and stem cell transplantation are often pivoted on MRD status. Relapse rates are high even with the integration of firstgeneration FMS-like tyrosine kinase 3 (FLT3) inhibitors in pre-and posttransplant regimes and as maintenance in FLT3-mutated AML. Pre-clinical progress is hampered by the lack of suitable modelling of residual disease and post-therapy relapse. In the present study, we investigated the nature of pro-survival signalling in primary residual tyrosine kinase inhibitor (TKI)-treated AML cells adherent to stroma and further determined their drug sensitivity in order to inform rational future therapy combinations. Using a primary human leukaemia-human stroma model to mimic the cell-cell interactions occurring in patients, the ability of several TKIs in clinical use, to abrogate stroma-driven leukaemic signalling was determined, and a synergistic combination with a mitogen-activated protein kinase (MEK) inhibitor identified for potential therapeutic application in the MRD setting. The findings reveal a common mechanism of stroma-mediated resistance that may be independent of mutational status but can be targeted through rational drug design, to eradicate MRD and reduce treatment-related toxicity.

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“…Its knockdown results in impairment of LSC homing (specifically to the bone marrow endosteal surface), downregulation of an LSC transcriptional programme, and induced differentiation [17]. ITGB3 is upregulated in the CD34 + CD38blast subset [35] and has been implicated in chemoresistance [36]. Osteopontin can augment ITGB3-mediated spreading and signal transduction [20].…”

Section: Discussionmentioning

confidence: 99%

Molecular Signature of Dormancy in CD34+CD38- Acute Myeloid Leukaemia Cells

Al-Asadi

Castellanos

May

et al. 2016

Blood

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Chemotherapy drugs tend to spare cells in a state of dormancy (G0 phase of the cell cycle). Relapse of acute myeloid leukaemia (AML) is likely in part due to dormant cells evading remission-induction chemotherapy. Dormant AML cells have been identified in the bone marrow endosteal region which is characterised by an excess of TGFβ1 and a shortage of nutrients. We developed and characterized an in-vitro model of AML cell dormancy by exploiting these features. Following preliminary investigation of several cell lines, the CD34+CD38- line TF1a was selected for in depth investigation. TF1a cells showed 72% inhibition of proliferation (p<0.001), with features of dormancy, in response to 72 hours TGFβ1+mTOR inhibitor treatment (mTOR pathway inhibition mimics major effects of nutrient scarcity).This treatment caused loss of Ki-67, as well as upregulating ALDH and CD34 and causing nuclear translocation of FOXO3a. In contrast to conventional serum-withdrawal assays for dormancy, the treatment had no impact on cell viability, assessed by Annexin V assay. Nor did the treatment lead to cell differentiation, assessed by CD11b staining and morphology. Using whole human genome expression microarray and by intersecting differentially regulated genes in dormancy-induced TF1a cells in comparison to their proliferating (untreated) counterparts, we identified 240 genes which are significantly up-regulated >2 fold including genes involved in stemness, chemoresistance and tumour suppressor genes in addition to genes involved in canonical cell cycle regulation. There was striking upregulation of genes involved in adhesion and migration: raised expression levels of SPP1 (the gene coding for osteopontin), ITGB3, ITGB4, ITGA3 and CD44 in dormant cells were confirmed by real-time PCR. The most upregulated gene was SPP1/osteopontin (16 fold). Immunocytochemistry of biopsy material from AML patients confirmed high levels of osteopontin in the cytoplasm of blasts near the paratrabecular bone marrow. Osteopontin and other genes identified in this model, including well-characterised genes (e.g. CD44, CD47, CD123, ABBC3 and CDKN2B) as well as little-known ones (e.g. PTPRU, ITGB3 and BTG2), are potential therapeutic targets in dormant AML cells. Disclosures No relevant conflicts of interest to declare.

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Integrin alphavbeta3 enhances β-catenin signaling in acute myeloid leukemia harboring Fms-like tyrosine kinase-3 internal tandem duplication mutations: implications for microenvironment influence on sorafenib sensitivity

Cited by 46 publications

References 30 publications

The bone marrow microenvironment in health and disease at a glance

The bone marrow microenvironment in health and disease at a glance

Combination of a mitogen‐activated protein kinase inhibitor with the tyrosine kinase inhibitor pacritinib combats cell adhesion‐based residual disease and prevents re‐expansion of FLT3‐ITD acute myeloid leukaemia

Molecular Signature of Dormancy in CD34+CD38- Acute Myeloid Leukaemia Cells

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