Sairavish Akkineni

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.

Works Cited.

1. 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
2. Zhong Z, Virshup DM. Wnt Signaling and Drug Resistance in Cancer. Mol Pharmacol. 2020;97(2):72-89. doi:10.1124/mol.119.117978
3. 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
4. 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
5. Newell LF, Cook RJ. Advances in acute myeloid leukemia. BMJ. 2021;375:n2026. Published 2021 Oct 6. doi:10.1136/bmj.n2026
6. 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
7. 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
8. 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
9. 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
10. 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
11. 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
12. 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