Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Acute lymphoblastic leukemia

GSK-3: a multifaceted player in acute leukemias

Leukemia volume 35, pages 1829–1842 (2021)Cite this article

Subjects

Abstract

Glycogen synthase kinase 3 (GSK-3) consists of two isoforms (α and β) that were originally linked to glucose metabolism regulation. However, GSK-3 is also involved in several signaling pathways controlling many different key functions in healthy cells. GSK-3 is a unique kinase in that its isoforms are constitutively active, while they are inactivated mainly through phosphorylation at Ser residues by a variety of upstream kinases. In the early 1990s, GSK-3 emerged as a key player in cancer cell pathophysiology. Since active GSK-3 promotes destruction of multiple oncogenic proteins (e.g., β-catenin, c-Myc, Mcl-1) it was considered to be a tumor suppressor. Accordingly, GSK-3 is frequently inactivated in human cancer via aberrant regulation of upstream signaling pathways. More recently, however, it has emerged that GSK-3 isoforms display also oncogenic properties, as they up-regulate pathways critical for neoplastic cell proliferation, survival, and drug-resistance. The regulatory roles of GSK-3 isoforms in cell cycle, apoptosis, DNA repair, tumor metabolism, invasion, and metastasis reflect the therapeutic relevance of these kinases and provide the rationale for combining GSK-3 inhibitors with other targeted drugs. Here, we discuss the multiple and often conflicting roles of GSK-3 isoforms in acute leukemias. We also review the current status of GSK-3 inhibitor development for innovative leukemia therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Structural domains and regulation of GSK-3 isoform activity.
Fig. 2: GSK-3 is a critical negative regulator of β-catenin/WNT signaling.
Fig. 3: Nuclear GSK-3β increases NF-kB-dependent transcription of Bcl-xL and XIAP.
Fig. 4: The transcription factor PU.1 is a substrate of GSK-3β in human AML cell lines.
Fig. 5: Wnt/STOP signaling activation sensitizes ALL cells to asparaginase via inactivation of GSK-3α.

Similar content being viewed by others

References

  1. Yeaman SJ, Armstrong JL, Bonavaud SM, Poinasamy D, Pickersgill L, Halse R. Regulation of glycogen synthesis in human muscle cells. Biochem Soc Trans. 2001;29:537–41.

    Article  CAS  PubMed  Google Scholar 

  2. McCubrey JA, Rakus D, Gizak A, Steelman LS, Abrams SL, Lertpiriyapong K, et al. Effects of mutations in Wnt/β-catenin, hedgehog, Notch and PI3K pathways on GSK-3 activity-Diverse effects on cell growth, metabolism and cancer. Biochim Biophys Acta. 2016;1863:2942–76.

    Article  CAS  PubMed  Google Scholar 

  3. Dey S, Brothag C, Vijayaraghavan S. Signaling enzymes required for sperm maturation and fertilization in mammals. Front Cell Dev Biol. 2019;7:341.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ahmad F, Woodgett JR. Emerging roles of GSK-3α in pathophysiology: emphasis on cardio-metabolic disorders. Biochim Biophys Acta-Mol Cell Res. 2020;1867:118616.

    Article  CAS  PubMed  Google Scholar 

  5. Nagini S, Sophia J, Mishra R. Glycogen synthase kinases: moonlighting proteins with theranostic potential in cancer. Semin Cancer Biol. 2019;56:25–36.

    Article  CAS  PubMed  Google Scholar 

  6. Cole AR. GSK3 as a sensor determining cell fate in the brain. Front Mol Neurosci. 2012;5:4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cervello M, Augello G, Cusimano A, Emma MR, Balasus D, Azzolina A, et al. Pivotal roles of glycogen synthase-3 in hepatocellular carcinoma. Adv Biol Regul. 2017;65:59–76.

    Article  CAS  PubMed  Google Scholar 

  8. Itoh S, Saito T, Hirata M, Ushita M, Ikeda T, Woodgett JR, et al. GSK-3α and GSK-3β proteins are involved in early stages of chondrocyte differentiation with functional redundancy through RelA protein phosphorylation. J Biol Chem. 2012;287:29227–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kerkela R, Kockeritz L, Macaulay K, Zhou J, Doble BW, Beahm C, et al. Deletion of GSK-3β in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation. J Clin Invest. 2008;118:3609–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yang K, Chen Z, Gao J, Shi W, Li L, Jiang S, et al. The Key roles of GSK-3β in regulating mitochondrial activity. Cell Physiol Biochem. 2017;44:1445–59.

    Article  CAS  PubMed  Google Scholar 

  11. Bechard M, Dalton S. Subcellular localization of glycogen synthase kinase 3β controls embryonic stem cell self-renewal. Mol Cell Biol. 2009;29:2092–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Evangelisti C, Chiarini F, Paganelli F, Marmiroli S, Martelli AM. Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer. Biochim Biophys Acta-Mol Cell Res. 2020;1867:118635.

    Article  CAS  PubMed  Google Scholar 

  13. Ignatz-Hoover JJ, Wang V, Mackowski NM, Roe AJ, Ghansah IK, Ueda M, et al. Aberrant GSK3β nuclear localization promotes AML growth and drug resistance. Blood Adv. 2018;2:2890–2903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hu Y, Gu X, Li R, Luo Q, Xu Y. Glycogen synthase kinase-3β inhibition induces nuclear factor-κB-mediated apoptosis in pediatric acute lymphocyte leukemia cells. J Exp Clin Cancer Res. 2010;29:154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Goc A, Al-Husein B, Katsanevas K, Steinbach A, Lou U, Sabbineni H, et al. Targeting Src-mediated Tyr216 phosphorylation and activation of GSK-3 in prostate cancer cells inhibit prostate cancer progression in vitro and in vivo. Oncotarget. 2014;5:775–87.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Takahashi-Yanaga F, Shiraishi F, Hirata M, Miwa Y, Morimoto S, Sasaguri T. Glycogen synthase kinase-3β is tyrosine-phosphorylated by MEK1 in human skin fibroblasts. Biochem Biophys Res Commun. 2004;316:411–5.

    Article  CAS  PubMed  Google Scholar 

  17. Dajani R, Fraser E, Roe SM, Young N, Good V, Dale TC, et al. Crystal structure of glycogen synthase kinase 3 β: structural basis for phosphate-primed substrate specificity and autoinhibition. Cell. 2001;105:721–32.

    Article  CAS  PubMed  Google Scholar 

  18. Kaidanovich-Beilin O, Woodgett JR. GSK-3: functional Insights from Cell Biology and Animal Models. Front Mol Neurosci. 2011;4:40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chiara F, Rasola A. GSK-3 and mitochondria in cancer cells. Front Oncol. 2013;3:16.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lambrecht C, Libbrecht L, Sagaert X, Pauwels P, Hoorne Y, Crowther J, et al. Loss of protein phosphatase 2A regulatory subunit B56δ promotes spontaneous tumorigenesis in vivo. Oncogene. 2018;37:544–52.

    Article  CAS  PubMed  Google Scholar 

  21. Tang XL, Wang CN, Zhu XY, Ni X. Protein tyrosine phosphatase SHP-1 modulates osteoblast differentiation through direct association with and dephosphorylation of GSK3β. Mol Cell Endocrinol. 2017;439:203–12.

    Article  CAS  PubMed  Google Scholar 

  22. de Groot RP, Auwerx J, Bourouis M, Sassone-Corsi P. Negative regulation of Jun/AP-1: conserved function of glycogen synthase kinase 3 and the Drosophila kinase shaggy. Oncogene. 1993;8:841–7.

    PubMed  Google Scholar 

  23. Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P. Binding of GSK3β to the APC-β-catenin complex and regulation of complex assembly. Science. 1996;272:1023–6.

    Article  CAS  PubMed  Google Scholar 

  24. Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 1998;12:3499–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Leis H, Segrelles C, Ruiz S, Santos M, Paramio JM. Expression, localization, and activity of glycogen synthase kinase 3β during mouse skin tumorigenesis. Mol Carcinog. 2002;35:180–5.

    Article  CAS  PubMed  Google Scholar 

  26. Tong J, Wang P, Tan S, Chen D, Nikolovska-Coleska Z, Zou F, et al. Mcl-1 degradation is required for targeted therapeutics to eradicate colon cancer cells. Cancer Res. 2017;77:2512–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shin S, Wolgamott L, Yu Y, Blenis J, Yoon SO. Glycogen synthase kinase (GSK)-3 promotes p70 ribosomal protein S6 kinase (p70S6K) activity and cell proliferation. Proc Natl Acad Sci USA. 2011;108:E1204–13.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Shin S, Wolgamott L, Tcherkezian J, Vallabhapurapu S, Yu Y, Roux PP, et al. Glycogen synthase kinase-3β positively regulates protein synthesis and cell proliferation through the regulation of translation initiation factor 4E-binding protein 1. Oncogene. 2014;33:1690–9.

    Article  CAS  PubMed  Google Scholar 

  29. Robertson H, Hayes JD, Sutherland C. A partnership with the proteasome; the destructive nature of GSK3. Biochem Pharm. 2018;147:77–92.

    Article  CAS  PubMed  Google Scholar 

  30. Dajani R, Fraser E, Roe SM, Yeo M, Good VM, Thompson V, et al. Structural basis for recruitment of glycogen synthase kinase 3β to the axin-APC scaffold complex. EMBO J. 2003;22:494–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Stamos JL, Weis WI. The β-catenin destruction complex. Cold Spring Harb Perspect Biol. 2013;5:a007898.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Jung YS, Park JI. Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex. Exp Mol Med. 2020;52:183–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. McCubrey JA, Steelman LS, Bertrand FE, Davis NM, Abrams SL, Montalto G, et al. Multifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention. Leukemia. 2014;28:15–33.

    Article  CAS  PubMed  Google Scholar 

  34. Doble BW, Patel S, Wood GA, Kockeritz LK, Woodgett JR. Functional redundancy of GSK-3α and GSK-3β in Wnt/β-catenin signaling shown by using an allelic series of embryonic stem cell lines. Dev Cell. 2007;12:957–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wagner FF, Benajiba L, Campbell AJ, Weiwer M, Sacher JR, Gale JP, et al. Exploiting an Asp-Glu “switch” in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia. Sci Transl Med. 2018;10:eaam8460.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Kitanaka N, Hall FS, Uhl GR, Kitanaka J. Lithium pharmacology and a potential role of lithium on methamphetamine abuse and dependence. Curr Drug Res Rev. 2019;11:85–91.

    Article  CAS  PubMed  Google Scholar 

  37. Takahashi-Yanaga F. Activator or inhibitor? GSK-3 as a new drug target. Biochem Pharm. 2013;86:191–9.

    Article  CAS  PubMed  Google Scholar 

  38. Neumann T, Benajiba L, Goring S, Stegmaier K, Schmidt B. Evaluation of improved glycogen synthase kinase-3α inhibitors in models of acute myeloid leukemia. J Med Chem. 2015;58:8907–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang Y, Dou X, Jiang L, Jin H, Zhang L, Zhang L, et al. Discovery of novel glycogen synthase kinase-3α inhibitors: structure-based virtual screening, preliminary SAR and biological evaluation for treatment of acute myeloid leukemia. Eur J Med Chem. 2019;171:221–34.

    Article  CAS  PubMed  Google Scholar 

  40. Ding S, Wu TY, Brinker A, Peters EC, Hur W, Gray NS, et al. Synthetic small molecules that control stem cell fate. Proc Natl Acad Sci USA. 2003;100:7632–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jiang J, Zhao M, Zhang A, Yu M, Lin X, Wu M, et al. Characterization of a GSK-3 inhibitor in culture of human cord blood primitive hematopoietic cells. Biomed Pharmacother. 2010;64:482–6.

    Article  CAS  PubMed  Google Scholar 

  42. Tolosa E, Litvan I, Hoglinger GU, Burn D, Lees A, Andres MV, et al. A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy. Mov Disord. 2014;29:470–8.

    Article  CAS  PubMed  Google Scholar 

  43. Matsunaga S, Fujishiro H, Takechi H. Efficacy and safety of glycogen synthase kinase 3 inhibitors for Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis. 2019;69:1031–9.

    Article  CAS  PubMed  Google Scholar 

  44. del Ser T, Steinwachs KC, Gertz HJ, Andres MV, Gomez-Carrillo B, Medina M, et al. Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: a pilot study. J Alzheimers Dis. 2013;33:205–5.

    PubMed  Google Scholar 

  45. Gray JE, Infante JR, Brail LH, Simon GR, Cooksey JF, Jones SF, et al. A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin. Invest New Drugs. 2015;33:1187–96.

    Article  CAS  PubMed  Google Scholar 

  46. Ballin A, Lehman D, Sirota P, Litvinjuk U, Meytes D. Increased number of peripheral blood CD34+ cells in lithium-treated patients. Br J Haematol. 1998;100:219–21.

    Article  CAS  PubMed  Google Scholar 

  47. Boggs DR, Joyce RA. The hematopoietic effects of lithium. Semin Hematol. 1983;20:129–38.

    CAS  PubMed  Google Scholar 

  48. Joyce RA. Sequential effects of lithium on haematopoiesis. Br J Haematol. 1984;56:307–21.

    Article  CAS  PubMed  Google Scholar 

  49. Luis TC, Ichii M, Brugman MH, Kincade P, Staal FJ. Wnt signaling strength regulates normal hematopoiesis and its deregulation is involved in leukemia development. Leukemia. 2012;26:414–21.

    Article  CAS  PubMed  Google Scholar 

  50. Trowbridge JJ, Xenocostas A, Moon RT, Bhatia M. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nat Med. 2006;12:89–98.

    Article  CAS  PubMed  Google Scholar 

  51. Holmes T, O’Brien TA, Knight R, Lindeman R, Shen S, Song E, et al. Glycogen synthase kinase-3β inhibition preserves hematopoietic stem cell activity and inhibits leukemic cell growth. Stem Cells. 2008;26:1288–97.

    Article  CAS  PubMed  Google Scholar 

  52. Li J, Zhang L, Yin L, Ma N, Wang T, Wu Y, et al. In vitro expansion of hematopoietic stem cells by inhibition of both GSK3 and p38 signaling. Stem Cells Dev. 2019;28:1486–97.

    Article  CAS  PubMed  Google Scholar 

  53. Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med. 2006;12:446–51.

    Article  CAS  PubMed  Google Scholar 

  54. Huang J, Zhang Y, Bersenev A, O’Brien WT, Tong W, Emerson SG, et al. Pivotal role for glycogen synthase kinase-3 in hematopoietic stem cell homeostasis in mice. J Clin Invest. 2009;119:3519–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Huang J, Nguyen-McCarty M, Hexner EO, Danet-Desnoyers G, Klein PS. Maintenance of hematopoietic stem cells through regulation of Wnt and mTOR pathways. Nat Med. 2012;18:1778–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Guezguez B, Almakadi M, Benoit YD, Shapovalova Z, Rahmig S, Fiebig-Comyn A, et al. GSK3 deficiencies in hematopoietic stem cells initiate pre-neoplastic state that is predictive of clinical outcomes of human acute leukemia. Cancer Cell. 2016;29:61–74.

    Article  CAS  PubMed  Google Scholar 

  57. Patel SA, Gerber JM. A user’s guide to novel therapies for acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2020;20:277–88.

    Article  PubMed  Google Scholar 

  58. Shafer D, Grant S. Update on rational targeted therapy in AML. Blood Rev. 2016;30:275–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ruvolo PP, Qiu Y, Coombes KR, Zhang N, Neeley ES, Ruvolo VR, et al. Phosphorylation of GSK3α/β correlates with activation of AKT and is prognostic for poor overall survival in acute myeloid leukemia patients. Biochim Biophys Acta-Clin. 2015;4:59–68.

  60. Hou P, Wu C, Wang Y, Qi R, Bhavanasi D, Zuo Z, et al. A genome-wide CRISPR screen identifies genes critical for resistance to FLT3 inhibitor AC220. Cancer Res. 2017;77:4402–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wang Z, Smith KS, Murphy M, Piloto O, Somervaille TC, Cleary ML. Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy. Nature. 2008;455:1205–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Banerji V, Frumm SM, Ross KN, Li LS, Schinzel AC, Hahn CK, et al. The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia. J Clin Invest. 2012;122:935–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. He L, Fei DL, Nagiec MJ, Mutvei AP, Lamprakis A, Kim BY, et al. Regulation of GSK3 cellular location by FRAT modulates mTORC1-dependent cell growth and sensitivity to rapamycin. Proc Natl Acad Sci USA. 2019;116:19523–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Pradere JP, Hernandez C, Koppe C, Friedman RA, Luedde T, Schwabe RF. Negative regulation of NF-κB p65 activity by serine 536 phosphorylation. Sci Signal. 2016;9:ra85.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Mishra M, Thacker G, Sharma A, Singh AK, Upadhyay V, Sanyal S, et al. FBW7 inhibits myeloid differentiation in acute myeloid leukemia via GSK3-dependent ubiquitination of PU.1. Mol Cancer Res. 2021;19:261–73.

    Article  CAS  PubMed  Google Scholar 

  66. Song EY, Palladinetti P, Klamer G, Ko KH, Lindeman R, O’Brien TA, et al. Glycogen synthase kinase-3β inhibitors suppress leukemia cell growth. Exp Hematol. 2010;38:908–21.

    Article  CAS  PubMed  Google Scholar 

  67. Hu S, Ueda M, Stetson L, Ignatz-Hoover J, Moreton S, Chakrabarti A, et al. A novel glycogen synthase kinase-3 inhibitor optimized for acute myeloid leukemia differentiation activity. Mol Cancer Ther. 2016;15:1485–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gupta K, Stefan T, Ignatz-Hoover J, Moreton S, Parizher G, Saunthararajah Y, et al. GSK-3 inhibition sensitizes acute myeloid leukemia cells to 1,25D-mediated differentiation. Cancer Res. 2016;76:2743–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Takei H, Kobayashi SS. Targeting transcription factors in acute myeloid leukemia. Int J Hematol. 2019;109:28–34.

    Article  CAS  PubMed  Google Scholar 

  70. Antony-Debre I, Paul A, Leite J, Mitchell K, Kim HM, Carvajal LA, et al. Pharmacological inhibition of the transcription factor PU.1 in leukemia. J Clin Invest. 2017;127:4297–313.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Rosenbauer F, Wagner K, Kutok JL, Iwasaki H, Le Beau MM, Okuno Y, et al. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nat Genet. 2004;36:624–30.

    Article  CAS  PubMed  Google Scholar 

  72. Pianigiani G, Betti C, Bigerna B, Rossi R, Brunetti L. PU.1 subcellular localization in acute myeloid leukaemia with mutated NPM1. Br J Haematol. 2020;188:184–7.

    Article  PubMed  Google Scholar 

  73. He L, Gomes AP, Wang X, Yoon SO, Lee G, Nagiec MJ, et al. mTORC1 promotes metabolic reprogramming by the suppression of GSK3-dependent Foxk1 phosphorylation. Mol Cell. 2018;70:949–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 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;236:570–86.

    Article  CAS  PubMed  Google Scholar 

  75. Rizzieri DA, Cooley S, Odenike O, Moonan L, Chow KH, Jackson K, et al. An open-label phase 2 study of glycogen synthase kinase-3 inhibitor LY2090314 in patients with acute leukemia. Leuk Lymphoma. 2016;57:1800–6.

    Article  CAS  PubMed  Google Scholar 

  76. Thomas X. Acute promyelocytic leukemia: a history over 60 years-from the most malignant to the most curable form of acute leukemia. Oncol Ther. 2019;7:33–65.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Si J, Mueller L, Collins SJ. GSK3 inhibitors enhance retinoic acid receptor activity and induce the differentiation of retinoic acid-sensitive myeloid leukemia cells. Leukemia. 2011;25:1914–8.

    Article  CAS  PubMed  Google Scholar 

  78. Gupta K, Gulen F, Sun L, Aguilera R, Chakrabarti A, Kiselar J, et al. GSK3 is a regulator of RAR-mediated differentiation. Leukemia. 2012;26:1277–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Park S, Han HT, Oh SS, Kim DH, Jeong JW, Lee KW, et al. NDRG2 sensitizes myeloid leukemia to arsenic trioxide via GSK3β-NDRG2-PP2A complex formation. Cells. 2019;8:495.

    Article  CAS  PubMed Central  Google Scholar 

  80. Ueda M, Stefan T, Stetson L, Ignatz-Hoover JJ, Tomlinson B, Creger RJ, et al. Phase I trial of lithium and tretinoin for treatment of relapsed and refractory non-promyelocytic acute myeloid leukemia. Front Oncol. 2020;10:327.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Zassadowski F, Pokorna K, Ferre N, Guidez F, Llopis L, Chourbagi O, et al. Lithium chloride antileukemic activity in acute promyelocytic leukemia is GSK-3 and MEK/ERK dependent. Leukemia. 2015;29:2277–84.

    Article  CAS  PubMed  Google Scholar 

  82. Cancilla D, Rettig MP, DiPersio JF. Targeting CXCR4 in AML and ALL. Front Oncol. 2020;10:1672.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Hu K, Gu Y, Lou L, Liu L, Hu Y, Wang B, et al. Galectin-3 mediates bone marrow microenvironment-induced drug resistance in acute leukemia cells via Wnt/β-catenin signaling pathway. J Hematol Oncol. 2015;8:1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Takam Kamga P, Dal Collo G, Cassaro A, Bazzoni R, Delfino P, Adamo A, et al. Small molecule inhibitors of microenvironmental Wnt/β-catenin signaling enhance the chemosensitivity of acute myeloid leukemia. Cancers. 2020;12:2696.

    Article  PubMed Central  Google Scholar 

  85. Ruan Y, Kim HN, Ogana H, Kim YM. Wnt signaling in leukemia and its bone marrow microenvironment. Int J Mol Sci. 2020;21:6247.

    Article  CAS  PubMed Central  Google Scholar 

  86. Parameswaran R, Ramakrishnan P, Moreton SA, Xia Z, Hou Y, Lee DA, et al. Repression of GSK3 restores NK cell cytotoxicity in AML patients. Nat Commun. 2016;7:11154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Graham JA, Fray M, de Haseth S, Lee KM, Lian MM, Chase CM, et al. Suppressive regulatory T cell activity is potentiated by glycogen synthase kinase 3β inhibition. J Biol Chem. 2010;285:32852–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Saleh R, Elkord E. FoxP3+ T regulatory cells in cancer: prognostic biomarkers and therapeutic targets. Cancer Lett. 2020;490:174–85.

    Article  CAS  PubMed  Google Scholar 

  89. Vadillo E, Dorantes-Acosta E, Pelayo R, Schnoor M. T cell acute lymphoblastic leukemia (T-ALL): new insights into the cellular origins and infiltration mechanisms common and unique among hematologic malignancies. Blood Rev. 2018;32:36–51.

    Article  CAS  PubMed  Google Scholar 

  90. Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick NJ, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children’s oncology group. J Clin Oncol. 2012;30:1663–9.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, et al. Improved survival for children and young adults with t-lineage acute lymphoblastic leukemia: results from the children’s oncology group AALL0434 methotrexate randomization. J Clin Oncol. 2018;36:2926–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Raetz EA, Teachey DT. T-cell acute lymphoblastic leukemia. Hematol Am Soc Hematol Educ Program. 2016;2016:580–8.

    Article  Google Scholar 

  93. Gokbuget N. How should we treat a patient with relapsed Ph-negative B-ALL and what novel approaches are being investigated? Best Pract Res Clin Haematol. 2017;30:261–74.

    Article  PubMed  Google Scholar 

  94. Zhou F, Zhang L, van Laar T, van Dam H, Ten Dijke P. GSK3β inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb. Mol Biol Cell. 2011;22:3533–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Weathington NM, Snavely CA, Chen BB, Zhao J, Zhao Y, Mallampalli RK. Glycogen synthase kinase-3β stabilizes the interleukin (IL)-22 receptor from proteasomal degradation in murine lung epithelia. J Biol Chem. 2014;289:17610–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Wang XJ, Xu YH, Yang GC, Chen HX, Zhang P. Tetramethylpyrazine inhibits the proliferation of acute lymphocytic leukemia cell lines via decrease in GSK-3β. Oncol Rep. 2015;33:2368–74.

    Article  CAS  PubMed  Google Scholar 

  97. Tosello V, Bordin F, Yu J, Agnusdei V, Indraccolo S, Basso G, et al. Calcineurin and GSK-3 inhibition sensitizes T-cell acute lymphoblastic leukemia cells to apoptosis through X-linked inhibitor of apoptosis protein degradation. Leukemia. 2016;30:812–2.

    Article  CAS  PubMed  Google Scholar 

  98. Lee JU, Kim LK, Choi JM. Revisiting the concept of targeting NFAT to control T cell immunity and autoimmune diseases. Front Immunol. 2018;9:2747.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Radadiya A, Zhu W, Coricello A, Alcaro S, Richards NGJ. Improving the treatment of acute lymphoblastic leukemia. Biochemistry. 2020;59:3193–200.

    Article  CAS  PubMed  Google Scholar 

  100. Lee JK, Kang S, Wang X, Rosales JL, Gao X, Byun HG, et al. HAP1 loss confers l-asparaginase resistance in ALL by downregulating the calpain-1-Bid-caspase-3/12 pathway. Blood. 2019;133:2222–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Hinze L, Pfirrmann M, Karim S, Degar J, McGuckin C, Vinjamur D, et al. Synthetic lethality of Wnt pathway activation and asparaginase in drug-resistant acute leukemias. Cancer Cell. 2019;35:664–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Chiarini F, Paganelli F, Martelli AM, Evangelisti C. The role played by Wnt/β-catenin signaling pathway in acute lymphoblastic leukemia. Int J Mol Sci. 2020;21:1098.

    Article  CAS  PubMed Central  Google Scholar 

  103. Evangelisti C, Chiarini F, Cappellini A, Paganelli F, Fini M, Santi S, et al. Targeting Wnt/β-catenin and PI3K/Akt/mTOR pathways in T-cell acute lymphoblastic leukemia. J Cell Physiol. 2020;235:5413–28.

    Article  CAS  PubMed  Google Scholar 

  104. Borga C, Foster CA, Iyer S, Garcia SP, Langenau DM, Frazer JK. Molecularly distinct models of zebrafish Myc-induced B cell leukemia. Leukemia. 2019;33:559–62.

    Article  PubMed  Google Scholar 

  105. Galluzzi L, Spranger S, Fuchs E, Lopez-Soto A. WNT signaling in cancer immunosurveillance. Trends Cell Biol. 2019;29:44–65.

    Article  CAS  PubMed  Google Scholar 

  106. Nomura S, Takahashi H, Suzuki J, Kuwahara M, Yamashita M, Sawasaki T. Pyrrothiogatain acts as an inhibitor of GATA family proteins and inhibits Th2 cell differentiation in vitro. Sci Rep. 2019;9:17335.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Martin-Acosta P, Xiao X. PROTACs to address the challenges facing small molecule inhibitors. Eur J Med Chem. 2021;210:112993.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

    Alberto M. Martelli, Camilla Evangelisti & Francesca Paganelli

  2. CNR Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza” Unit of Bologna, Bologna, Italy

    Francesca Paganelli & Francesca Chiarini

  3. IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy

    Francesca Paganelli & Francesca Chiarini

  4. Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA

    James A. McCubrey

Authors
  1. Alberto M. Martelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Camilla Evangelisti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesca Paganelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francesca Chiarini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. James A. McCubrey
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AMM contributed to the literature search data and wrote the paper. FP, CE, and FC contributed to the literature search and drew the figures. JAM was responsible for the concept and critical revision of this paper.

Corresponding author

Correspondence to James A. McCubrey.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martelli, A.M., Evangelisti, C., Paganelli, F. et al. GSK-3: a multifaceted player in acute leukemias. Leukemia 35, 1829–1842 (2021). https://doi.org/10.1038/s41375-021-01243-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-021-01243-z

This article is cited by

Search

Advanced search

Quick links