Pharmacological targeting of  -catenin in normal karyotype acute myeloid leukemia blasts

Griffiths, Elizabeth A.; Golding, Michelle; Srivastava, Pragya; Povinelli, Benjamin; James, Smitha R.; Ford, Laurie; Wetzler, Meir; Wang, Eunice S.; Nemeth, Michael J.

doi:10.3324/haematol.2014.113118

Cited by 16 publications

(20 citation statements)

References 14 publications

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“…It is reasonable to deduce that the FLT3 inhibition should be the main contributor of the killing effect of SKLB-677 on AML cells. Despite that a number of studies have shown that Wnt/β-catenin pathway inhibitors could induce apoptosis in cultured AML cells 32 33 , we still can not definitely estimate whether the Wnt/β-catenin inhibition by SKLB-677 contributes to the killing effect on AML cells and how much it is. This is because of the discrepancies for the concentrations necessary to efficiently inhibit FLT3 and the Wnt/β-catenin signaling.…”

Section: Discussionmentioning

confidence: 95%

SKLB-677, an FLT3 and Wnt/β-catenin signaling inhibitor, displays potent activity in models of FLT3-driven AML

Yang

Niu

et al. 2015

Sci Rep

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FLT3 has been identified as a valid target for the treatment of acute myeloid leukemia (AML), and some FLT3 inhibitors have shown very good efficacy in treating AML in clinical trials. Nevertheless, recent studies indicated that relapse and drug resistance are still difficult to avoid, and leukemia stem cells (LSCs) are considered one of the most important contributors. Here, we report the characterization of SKLB-677, a new FLT3 inhibitor developed by us recently. SKLB-677 exhibits low nanomolar potency in biochemical and cellular assays. It is efficacious in animal models at doses as low as 1mg/kg when administrated orally once daily. In particular, SKLB-677 but not first-generation and second-generation FLT3 inhibitors in clinical trials has the ability to inhibit Wnt/β-catenin signaling; Wnt/β-catenin signaling is required for the development of LSCs, but not necessary for the development of adult hematopoietic stem cells (HSCs). This compound indeed showed considerable suppression effects on leukemia stem-like cells in in vitro functional assays, but had no influence on normal HSCs. Collectively, SKLB-677 is an interesting lead compound for the treatment of AML, and deserves further investigations.

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Section: Discussionmentioning

confidence: 95%

SKLB-677, an FLT3 and Wnt/β-catenin signaling inhibitor, displays potent activity in models of FLT3-driven AML

Yang

Niu

et al. 2015

Sci Rep

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“…As described above, this leukemia is based on an MLL-translocation and is dependent on Wnt-β-catenin signaling. However, several studies have demonstrated that Wnt-β-catenin is important also in AML with other genetic abnormalities, including del(5) [ 51 ], t(8;21) [ 52 ], normal karyotype AML [ 53 ], as well as FLT3-driven AML [ 52 ]. This pathway seems important for the survival of AML stem cells, and overexpression of this pathway has been associated with a poor prognosis in human AML [ 54 ].…”

Section: β3 Integrins and Spleen Tyrosine Kinase (Syk) Activation mentioning

confidence: 99%

The Possible Importance of β3 Integrins for Leukemogenesis and Chemoresistance in Acute Myeloid Leukemia

Johansen

Brenner

Bartaula-Brevik

et al. 2018

IJMS

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Acute myeloid leukemia (AML) is an aggressive bone marrow malignancy where the immature leukemia cells communicate with neighboring cells through constitutive cytokine release and through their cell surface adhesion molecules. The primary AML cells express various integrins. These heterodimeric molecules containing an α and a β chain are cell surface molecules that bind extracellular matrix molecules, cell surface molecules and soluble mediators. The β3 integrin (ITGB3) chain can form heterodimers only with the two α chains αIIb and αV. These integrins are among the most promiscuous and bind to a large number of ligands, including extracellular matrix molecules, cell surface molecules and soluble mediators. Recent studies suggest that the two β3 integrins are important for leukemogenesis and chemosensitivity in human AML. Firstly, αIIb and β3 are both important for adhesion of AML cells to vitronectin and fibronectin. Secondly, β3 is important for the development of murine AML and also for the homing and maintenance of the proliferation for xenografted primary human AML cells, and for maintaining a stem cell transcriptional program. These last effects seem to be mediated through Syk kinase. The β3 expression seems to be regulated by HomeboxA9 (HoxA9) and HoxA10, and the increased β3 expression then activates spleen tyrosine kinase (Syk) and thereby contributes to cytokine hypersensitivity and activation of β2 integrins. Finally, high integrin αV/β3 expression is associated with an adverse prognosis in AML and decreased sensitivity to the kinase inhibitor sorafenib; this integrin can also be essential for osteopontin-induced sorafenib resistance in AML. In the present article, we review the experimental and clinical evidence for a role of β3 integrins for leukemogenesis and chemosensitivity in AML.

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“…Several αvβ3 antibody and β-catenin inhibitors are under clinical trial in several cancer types [25–30]. Based on our study, these compounds might be considered as new pharmaceuticals for therapy of AML with FLT3-ITD mutation combined with TKIs.…”

Section: Discussionmentioning

confidence: 98%

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

Zeng

Shen

et al. 2016

Oncotarget

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Binding of leukemia cells to the bone marrow extracellular matrix (ECM) through integrins might influence drug response and the survival of acute myeloid leukemia (AML). However, the functions of integrin in AML are needed to be clarified. Data from The Cancer Genome Atlas (TCGA) were retrieved and integrin β3 (ITGB3) expression and prognostic significance for AML were analyzed. Integrin alphavbeta3 (αvβ3) in sorafenib sensitivity and signaling pathway of FLT3-ITD AML cells was evaluated in vitro. The level of ITGB3 expression was positively correlated with risk stratification and prognosis of AML patients, especially in cytogenetic-normal patients with Fms-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutation. Integrin αvβ3 decreased sorafenib sensitivity when co-culture of MV4-11 cells and bone marrow stromal cells (BMSCs), and it is crucial for osteopontin (OPN) induced sorafenib insensitivity in FLT3-ITD mutated AML cells. Mechanically, αvβ3 enhance β-catenin activation through phosphatidylinositol 3-kinase (PI3K)/Akt/Glycogen synthase kinase-3 beta (GSK3β) pathway. Moreover, genetic inhibition of β-catenin by shRNA could increase sorafenib sensitivity in MV4-11 cells. Taken together, our study revealed a novel mechanism in microenvironment influence on sorafenib sensitivity in AML with FLT3-ITD mutation that was caused by activating integrin αvβ3/PI3K/Akt/GSK3β/β-catenin pathway. Integrin αvβ3/β-catenin could be considered as a new therapeutic target for AML especially for FLT3-ITD mutated AML.

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Pharmacological targeting of -catenin in normal karyotype acute myeloid leukemia blasts

Cited by 16 publications

References 14 publications

SKLB-677, an FLT3 and Wnt/β-catenin signaling inhibitor, displays potent activity in models of FLT3-driven AML

SKLB-677, an FLT3 and Wnt/β-catenin signaling inhibitor, displays potent activity in models of FLT3-driven AML

The Possible Importance of β3 Integrins for Leukemogenesis and Chemoresistance in Acute Myeloid Leukemia

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

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