Targeting β-catenin in Acute Myeloid Leukaemia: Past, Present, and Future Perspectives

Overview

Journal Biosci Rep

Specialty Cell Biology

Date 2022 Mar 30

PMID 35352805

Authors

Megan Wagstaff

Brandon Coke

Georgia R Hodgkiss

Rhys G Morgan

Affiliations

Soon will be listed here.

Abstract

Acute myeloid leukaemia (AML) is an aggressive disease of the bone marrow with a poor prognosis. Evidence suggests long established chemotherapeutic regimens used to treat AML are reaching the limits of their efficacy, necessitating the urgent development of novel targeted therapies. Canonical Wnt signalling is an evolutionary conserved cascade heavily implicated in normal developmental and disease processes in humans. For over 15 years its been known that the central mediator of this pathway, β-catenin, is dysregulated in AML promoting the emergence, maintenance, and drug resistance of leukaemia stem cells. Yet, despite this knowledge, and subsequent studies demonstrating the therapeutic potential of targeting Wnt activity in haematological cancers, β-catenin inhibitors have not yet reached the clinic. The aim of this review is to summarise the current understanding regarding the role and mechanistic dysregulation of β-catenin in AML, and assess the therapeutic merit of pharmacologically targeting this molecule, drawing on lessons from other disease contexts.

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References

Luo H, Jing B, Xia Y, Zhang Y, Hu M, Cai H . WP1130 reveals USP24 as a novel target in T-cell acute lymphoblastic leukemia. Cancer Cell Int. 2019; 19:56. PMC: 6415346. DOI: 10.1186/s12935-019-0773-6. View

Kim I, Kwak H, Lee H, Hyun S, Jeong S . β-Catenin recognizes a specific RNA motif in the cyclooxygenase-2 mRNA 3'-UTR and interacts with HuR in colon cancer cells. Nucleic Acids Res. 2012; 40(14):6863-72. PMC: 3413138. DOI: 10.1093/nar/gks331. View

Giannini A, Vivanco M, Kypta R . alpha-catenin inhibits beta-catenin signaling by preventing formation of a beta-catenin*T-cell factor*DNA complex. J Biol Chem. 2000; 275(29):21883-8. DOI: 10.1074/jbc.M001929200. View

Lee D, Nathan Grantham R, Trachte A, Mannion J, Wilson C . Activation of the canonical Wnt/beta-catenin pathway enhances monocyte adhesion to endothelial cells. Biochem Biophys Res Commun. 2006; 347(1):109-16. DOI: 10.1016/j.bbrc.2006.06.082. View

Lane S, Sykes S, Al-Shahrour F, Shterental S, Paktinat M, Lo Celso C . The Apc(min) mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS. Blood. 2010; 115(17):3489-97. PMC: 2867262. DOI: 10.1182/blood-2009-11-251728. View

Morgan R, Pearn L, Liddiard K, Pumford S, Burnett A, Tonks A . γ-Catenin is overexpressed in acute myeloid leukemia and promotes the stabilization and nuclear localization of β-catenin. Leukemia. 2012; 27(2):336-43. PMC: 3613703. DOI: 10.1038/leu.2012.221. View

Gebauer F, Schwarzl T, Valcarcel J, Hentze M . RNA-binding proteins in human genetic disease. Nat Rev Genet. 2020; 22(3):185-198. DOI: 10.1038/s41576-020-00302-y. View

Jung Y, Park J . Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex. Exp Mol Med. 2020; 52(2):183-191. PMC: 7062731. DOI: 10.1038/s12276-020-0380-6. View

Zheng X, Beissert T, Kukoc-Zivojnov N, Puccetti E, Altschmied J, Strolz C . Gamma-catenin contributes to leukemogenesis induced by AML-associated translocation products by increasing the self-renewal of very primitive progenitor cells. Blood. 2004; 103(9):3535-43. DOI: 10.1182/blood-2003-09-3335. View

10.

Morgan R, Liddiard K, Pearn L, Pumford S, Burnett A, Darley R . γ-Catenin is expressed throughout normal human hematopoietic development and is required for normal PU.1-dependent monocyte differentiation. Leukemia. 2013; 27(10):2096-100. DOI: 10.1038/leu.2013.96. View

11.

Luis T, Ichii M, Brugman M, Kincade P, Staal F . Wnt signaling strength regulates normal hematopoiesis and its deregulation is involved in leukemia development. Leukemia. 2011; 26(3):414-21. PMC: 3378318. DOI: 10.1038/leu.2011.387. View

12.

Griffiths E, Golding M, Srivastava P, Povinelli B, James S, Ford L . Pharmacological targeting of β-catenin in normal karyotype acute myeloid leukemia blasts. Haematologica. 2014; 100(2):e49-52. PMC: 4803144. DOI: 10.3324/haematol.2014.113118. View

13.

Lee H, Jeong S . Beta-Catenin stabilizes cyclooxygenase-2 mRNA by interacting with AU-rich elements of 3'-UTR. Nucleic Acids Res. 2006; 34(19):5705-14. PMC: 1636482. DOI: 10.1093/nar/gkl698. View

14.

Morgan R, Ridsdale J, Tonks A, Darley R . Factors affecting the nuclear localization of β-catenin in normal and malignant tissue. J Cell Biochem. 2014; 115(8):1351-61. DOI: 10.1002/jcb.24803. View

15.

Saenz D, Fiskus W, Manshouri T, Mill C, Qian Y, Raina K . Targeting nuclear β-catenin as therapy for post-myeloproliferative neoplasm secondary AML. Leukemia. 2018; 33(6):1373-1386. DOI: 10.1038/s41375-018-0334-3. View

16.

Stroopinsky D, Rajabi H, Nahas M, Rosenblatt J, Rahimian M, Pyzer A . MUC1-C drives myeloid leukaemogenesis and resistance to treatment by a survivin-mediated mechanism. J Cell Mol Med. 2018; 22(8):3887-3898. PMC: 6050463. DOI: 10.1111/jcmm.13662. View

17.

Lane S, Wang Y, Lo Celso C, Ragu C, Bullinger L, Sykes S . Differential niche and Wnt requirements during acute myeloid leukemia progression. Blood. 2011; 118(10):2849-56. PMC: 3172801. DOI: 10.1182/blood-2011-03-345165. View

18.

Ming M, Wang S, Wu W, Senyuk V, Le Beau M, Nucifora G . Activation of Wnt/β-catenin protein signaling induces mitochondria-mediated apoptosis in hematopoietic progenitor cells. J Biol Chem. 2012; 287(27):22683-90. PMC: 3391123. DOI: 10.1074/jbc.M112.342089. View

19.

Simon M, Grandage V, Linch D, Khwaja A . Constitutive activation of the Wnt/beta-catenin signalling pathway in acute myeloid leukaemia. Oncogene. 2005; 24(14):2410-20. DOI: 10.1038/sj.onc.1208431. View

20.

Zhang Y, Wang J, Wheat J, Chen X, Jin S, Sadrzadeh H . AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/β-catenin signaling pathway. Blood. 2013; 121(24):4906-16. PMC: 3682341. DOI: 10.1182/blood-2012-08-447763. View