β-Catenin Dependent Signaling in Drug Resistant Acute Myeloid Leukemia
Background: Acute Myeloid Leukemia (AML) is a lethal hematopoietic disease associated with increased proliferation of immature myeloid cells and bone marrow failure.1 There are approximately 21 thousand new cases annually which represent 1.2 percent of all cancer diagnosis. The 5-year survival rate is 28.3 percent with a 40 percent chance of relapse due to beta-catenin pathway resistance.5,6 It appears that the β-Catenin pathway plays a significant role in drug resistance and poor prognosis of AML by maintaining the leukemia stem cells and enhancing their regeneration – causing patients to be stuck in the disease state.1,2 Currently, physical clinical findings are vague and range from asymptomatic to fever, pallor, illness and providers rely on blood samples and bone marrow biopsy to make definitive diagnosis.5 The current standard treatment is known as the 7+ 3 treatment which consists of 7 days of anthracycline and 3 days of daunorubicin.5 Patients experiencing remission are recommended to take fludarabine, cytarabine, granulocyte stimulating factor, and idarubicin (FLAG + Ida) .5 In addition, newer treatment plans have been incorporated, such as clonal hematopoiesis, consolidation therapy, novel agents, hypomethylating agents and low dose chemotherapy, B cell lymphoma-2 inhibition, and FLT3 inhibition.5 However, a key problem remains – AML is highly treatment/drug resistant and able to preserve leukemia stem cells through the β-Catenin pathway.1,2
Objective: This meta-analysis explored the etiology of the AML to better understand the relationship between drug resistance and the Wnt Pathway, as well as review novel clinical solutions.
Search Methods: Articles were sourced via PubMed database using keywords such as “AML, GSK3 beta, drug resistance, PI3K/Mtor”. Furthermore, articles were restricted to 2018 – present.
Results: The studies suggest that GSK3-beta is a key modulator in the beta-catenin pathway. Nuclear GSK3-beta causes transcriptional changes in PU.1 gene that are associated with worse prognosis and drug resistance.2 However, the inactivation results in AML growth inhibition and myeloid differentiation (i.e trending back to normal).2 Meanwhile, higher levels of cytosolic GSK3-beta was found to reduce rates of AML in patients when looking at cell markers via ubiquitination of beta-catenin, while lower levels of cytosolic GSK3-beta were associated with apoptosis.1,8 Additionally, Co-targeting upstream regulators such as PI3k/AKT/mTOR with the Wnt/Beta-catenin pathway is an aggressive treatment option that could reduce drug resistance in AML and be expanded to different neoplasia utilizing the same β-Catenin pathway.4 Ultimately, high levels of Beta-catenin are associated with worse prognosis and drug resistance.1
Conclusion: Beta-catenin pathway plays a significant role in the growth and drug resistance in multiple types of cancers – not just restricted to AML. It has the potential to be the site of clinical intervention for several neoplasms and is a promising pathway for future medical intervention and treatment. Future studies should analyze the varying roles of GSK3-beta in hopes of expanding treatment options to differing classes of cancers through modulation of the GSK3-beta/AKT interactions.
- Shahid AM, Um IH, Elshani M, Zhang Y, Harrison DJ. NUC-7738 regulates β-catenin signalling resulting in reduced proliferation and self-renewal of AML cells. PLoS One. 2022;17(12):e0278209. Published 2022 Dec 15. doi:10.1371/journal.pone.0278209
- Zhong Z, Virshup DM. Wnt Signaling and Drug Resistance in Cancer. Mol Pharmacol. 2020;97(2):72-89. doi:10.1124/mol.119.117978
- Bugter JM, Fenderico N, Maurice MM. Mutations and mechanisms of WNT pathway tumour suppressors in cancer [published correction appears in Nat Rev Cancer. 2020 Nov 4;:]. Nat Rev Cancer. 2021;21(1):5-21. doi:10.1038/s41568-020-00307-z
- Parsons MJ, Tammela T, Dow LE. WNT as a Driver and Dependency in Cancer. Cancer Discov. 2021;11(10):2413-2429. doi:10.1158/2159-8290.CD-21-0190
- Newell LF, Cook RJ. Advances in acute myeloid leukemia. BMJ. 2021;375:n2026. Published 2021 Oct 6. doi:10.1136/bmj.n2026
- DiNardo CD, Lachowiez CA, Takahashi K, et al. Venetoclax Combined With FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed or Refractory Acute Myeloid Leukemia. J Clin Oncol. 2021;39(25):2768-2778. doi:10.1200/JCO.20.03736
- Mishra M, Thacker G, Sharma A, et al. FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1. Mol Cancer Res. 2021;19(2):261-273. doi:10.1158/1541-7786.MCR-20-0268
- Lee YC, Shi YJ, Wang LJ, Chiou JT, Huang CH, Chang LS. GSK3β suppression inhibits MCL1 protein synthesis in human acute myeloid leukemia cells. J Cell Physiol. 2021;236(1):570-586. doi:10.1002/jcp.29884
- Evangelisti C, Chiarini F, Cappellini A, et al. Targeting Wnt/β-catenin and PI3K/Akt/mTOR pathways in T-cell acute lymphoblastic leukemia. J Cell Physiol. 2020;235(6):5413-5428. doi:10.1002/jcp.29429
- Huang D, Wang Y, Thompson JW, et al. Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression. Nat Cell Biol. 2022;24(2):230-241. doi:10.1038/s41556-021-00820-9
- Kitagishi Y, Kobayashi M, Kikuta K, Matsuda S. Roles of PI3K/AKT/GSK3/mTOR Pathway in Cell Signaling of Mental Illnesses. Depress Res Treat. 2012;2012:752563. doi:10.1155/2012/752563
- Ignatz-Hoover JJ, Wang V, Mackowski NM, et al. Aberrant GSK3β nuclear localization promotes AML growth and drug resistance. Blood Adv. 2018;2(21):2890-2903. doi:10.1182/bloodadvances.2018016006