The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia
Open accessAbstract
Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Long-term survival of patients with AML has changed little over the past decade, necessitating the identification and validation of new AML targets. Integration of genomic approaches with small-molecule and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. Here, we identified a role for glycogen synthase kinase 3α (GSK-3α) in AML by performing 2 independent small-molecule library screens and an shRNA screen for perturbations that induced a differentiation expression signature in AML cells. GSK-3 is a serine-threonine kinase involved in diverse cellular processes, including differentiation, signal transduction, cell cycle regulation, and proliferation. We demonstrated that specific loss of GSK-3α induced differentiation in AML by multiple measurements, including induction of gene expression signatures, morphological changes, and cell surface markers consistent with myeloid maturation. GSK-3α-specific suppression also led to impaired growth and proliferation in vitro, induction of apoptosis, loss of colony formation in methylcellulose, and anti-AML activity in vivo. Although the role of GSK-3β has been well studied in cancer development, these studies support a role for GSK-3α in AML.
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GSK3β inhibition promotes myeloid differentiation and apoptosis in leukemia cells.
“GSK3b inhibition promotes myeloid differentiation and apoptosis in leukemia cells (27)(28)(29)(30); however, mechanisms underlying GSK3b inhibition leading to myeloid differentiation are poorly understood.”
From FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1 (2021) · cites this paper as [27]
In “Loss of GSK-3α leads to differentiation of AML cells in vitro” (page unavailable), the paper reports that GSK-3β suppression was not enriched for monocyte-differentiation gene sets; it attributes the differentiation effect to GSK-3α suppression. In “Loss of GSK-3α decreases AML cell growth and proliferation” (page unavailable), it likewise reports apoptosis after GSK-3α suppression, not GSK-3β suppression. (LLM, conf=0.88)
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Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Döhner, H., Estey, E. H., Amadori, S., Appelbaum, F. R., Büchner, T., Burnett, A. K., Dombret, H., Fenaux, P., Grimwade, D. J., Larson, R. A., et al. (2009) · Blood · doi:10.1182/blood-2009-07-235358 · Cited by 3,348 · see citing works
Recurring mutations found by sequencing an acute myeloid leukemia genome
Mardis, E. R., Ding, L., Dooling, D. J., Larson, D. E., McLellan, M. D., Chen, K., Koboldt, D. C., Fulton, R. S., Delehaunty, K. D., McGrath, S. D., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0903840 · Cited by 2,219 · see citing works
GSK-3: tricks of the trade for a multi-tasking kinase
Doble, B. W., & Woodgett, J. R. (2003) · Journal of Cell Science · doi:10.1242/jcs.00384 · Cited by 2,084 · see citing works
<i>DNMT3A</i> Mutations in Acute Myeloid Leukemia
Ley, T. J., Ding, L., Walter, M. J., McLellan, M. D., Lamprecht, T., Larson, D. E., Kandoth, C., Payton, J. E., Baty, J., Welch, J., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1005143 · Cited by 1,983 · see citing works
RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia
Zuber, J., Shi, J., Wang, E., Rappaport, A. R., Herrmann, H., Sison, E. A., Magoon, D., Qi, J., Blatt, K., Wunderlich, M., et al. (2011) · Nature · doi:10.1038/nature10334 · Cited by 1,870 · see citing works
Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB
Beg, A. A., Sha, W. C., Bronson, R. T., Ghosh, S., & Baltimore, D. (1995) · Nature · doi:10.1038/376167a0 · Cited by 1,828 · see citing works
A Lentiviral RNAi Library for Human and Mouse Genes Applied to an Arrayed Viral High-Content Screen
Moffat, J., Grueneberg, D. A., Yang, X., Kim, S. Y., Kloepfer, A. M., Hinkle, G., Piqani, B., Eisenhaure, T., Luo, B., Grenier, J. K., et al. (2006) · Cell · doi:10.1016/j.cell.2006.01.040 · Cited by 1,803 · see citing works
Self-citationCohen, P., & Frame, S. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35096075 · Cited by 1,478 · see citing works
GSK3 takes centre stage more than 20 years after its discovery
FRAME, S., & COHEN, P. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3590001 · Cited by 1,433 · see citing works
Requirement for glycogen synthase kinase-3β in cell survival and NF-κB activation
Hoeflich, K. P., Luo, J., Rubie, E. A., Tsao, M., Jin, O., & Woodgett, J. R. (2000) · Nature · doi:10.1038/35017574 · Cited by 1,394 · see citing works
The GSK3 hypothesis of Alzheimer’s disease
Hooper, C., Killick, R., & Lovestone, S. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05194.x · Cited by 1,191 · see citing works
Densely Interconnected Transcriptional Circuits Control Cell States in Human Hematopoiesis
Novershtern, N., Subramanian, A., Lawton, L. N., Mak, R. H., Haining, W. N., McConkey, M. E., Habib, N., Yosef, N., Chang, C. Y., Shay, T., et al. (2011) · Cell · doi:10.1016/j.cell.2011.01.004 · Cited by 942 · see citing works
The Wnt/β-catenin Pathway Is Required for the Development of Leukemia Stem Cells in AML
Wang, Y., Krivtsov, A., Sinha, A., North, T., Goessling, W., Feng, Z.-H., Zon, L., & Armstrong, S. (2010) · Science · doi:10.1126/science.1186624 · Cited by 812 · see citing works
Doble, B. W., Patel, S., Wood, G. A., Kockeritz, L. K., & Woodgett, J. R. (2007) · Developmental Cell · doi:10.1016/j.devcel.2007.04.001 · Cited by 449 · see citing works
Glycogen Synthase Kinase 3α-Specific Regulation of Murine Hepatic Glycogen Metabolism
MacAulay, K., Doble, B. W., Patel, S., Hansotia, T., Sinclair, E. M., Drucker, D. J., Nagy, A., & Woodgett, J. R. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.08.013 · Cited by 296 · see citing works
Gene expression–based high-throughput screening(GE-HTS) and application to leukemia differentiation
Stegmaier, K., Ross, K. N., Colavito, S. A., et al. (2004) · Nature Genetics · doi:10.1038/ng1305 · Cited by 268 · see citing works
Self-citationGlycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy
Wang, Z., Smith, K. S., Murphy, M., Piloto, O., Somervaille, T. C. P., & Cleary, M. L. (2008) · Nature · doi:10.1038/nature07284 · Cited by 265 · see citing works
β-Catenin mediates the establishment and drug resistance of MLL leukemic stem cells.
Yeung, J., Esposito, M., Gandillet, A., Zeisig, B., Griessinger, E., Bonnet, D., & So, C. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.10.032 · Cited by 264 · see citing works
Glycogen synthase kinase 3β missplicing contributes to leukemia stem cell generation
Abrahamsson, A., Geron, I., Gotlib, J., Dao, K.-H. T., Barroga, C., Newton, I., Giles, F., Durocher, J., Creusot, R. S., Karimi, M., et al. (2009) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0900189106 · Cited by 264 · see citing works
Adès, L., Guerci‐Bresler, A., Raffoux, E., Sanz, M. Á., Chevallier, P., Lapusan, S., Récher, C., Thomas, X., Rayón, C., Castaigné, S., et al. (2009) · Blood · doi:10.1182/blood-2009-07-233387 · Cited by 250 · see citing works
Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation
Trowbridge, J. J., Xenocostas, A., Moon, R. T., & Bhatia, M. (2005) · Nature Medicine · doi:10.1038/nm1339 · Cited by 247 · see citing works
A method for high-throughput gene expression signature analysis
Peck, D., Crawford, E. D., Ross, K. N., Stegmaier, K., Golub, T. R., & Lamb, J. (2006) · Genome biology · doi:10.1186/gb-2006-7-7-r61 · Cited by 205 · see citing works
Self-citationOugolkov, A. V., Bone, N. D., Fernández-Zapico, M. E., Kay, N. E., & Billadeau, D. D. (2007) · Blood · doi:10.1182/blood-2006-12-060947 · Cited by 183 · see citing works
Abnormalities in brain structure and behavior in GSK-3alpha mutant mice
Kaidanovich‐Beilin, O., Lipina, T. V., Takao, K., van Eede, M., Hattori, S., Laliberté, C. L., Khan, M., Okamoto, K., Chambers, J. W., Fletcher, P. J., et al. (2009) · Molecular Brain · doi:10.1186/1756-6606-2-35 · Cited by 176 · see citing works
Proteomic and Genetic Approaches Identify Syk as an AML Target
Hahn, C. K., Berchuck, J. E., Ross, K. N., Kakoza, R. M., Clauser, K. R., Schinzel, A. C., Ross, L. S., Galinsky, I. A., Davis, T. N., Silver, S. J., et al. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.08.018 · Cited by 169 · see citing works
Self-citationGilliland, D. G. (2001) · Current Opinion in Hematology · doi:10.1097/00062752-200107000-00001 · Cited by 162 · see citing works
Rubnitz, J. E., Gibson, B. E. S., & Smith, F. O. (2010) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2009.11.008 · Cited by 159 · see citing works
Gould, T. D., Zarate, C. A., & Manji, H. K. (2004) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v65n0103 · Cited by 156 · see citing works
How do they do Wnt they do?: regulation of transcription by the Wnt/β‐catenin pathway
Archbold, H. C., Yang, Y., Chen, L., & Cadigan, K. M. (2011) · Acta Physiologica · doi:10.1111/j.1748-1716.2011.02293.x · Cited by 141 · see citing works
Glycogen Synthase Kinase 3: A Target for Novel Mood Disorder Treatments
Gould, T. D., & Manji, H. K. (2006) · doi:10.1002/0470052171.ch7 · Cited by 135 · see citing works
Pivotal role for glycogen synthase kinase–3 in hematopoietic stem cell homeostasis in mice
Huang, J. Y., Zhang, Y., Bersenev, A., O’Brien, W. T., Tong, W., Emerson, S. G., & Klein, P. S. (2009) · Journal of Clinical Investigation · doi:10.1172/jci40572 · Cited by 130 · see citing works
Targeting glycogen synthase kinase-3 (GSK-3) in the treatment of Type 2 diabetes
Macaulay, K., & Woodgett, J. (2008) · Expert opinion on therapeutic targets · doi:10.1517/14728222.12.10.1265 · Cited by 127 · see citing works
Wang, Z., 岩崎, 正., Ficara, F., Lin, C., Matheny, C., Wong, S. H. K., Smith, K. S., & Cleary, M. L. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.04.024 · Cited by 124 · see citing works
The clinical laboratory and electroencephalographic effects of lithium
Mayfield, D. G., & Brown, R. G. (1966) · Journal of Psychiatric Research · doi:10.1016/0022-3956(66)90008-2 · Cited by 121 · see citing works
Advances in Development of Phosphatidylinositol 3-Kinase Inhibitors
Kong, D., & Yamori, T. (2009) · Current Medicinal Chemistry · doi:10.2174/092986709788803222 · Cited by 112 · see citing works
Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma
Bilim, V. N., Ougolkov, A. V., Yuuki, K., Naito, S., Kawazoe, H., Muto, A., Oya, M., Billadeau, D. D., Motoyama, T., & Tomita, Y. (2009) · British Journal of Cancer · doi:10.1038/sj.bjc.6605437 · Cited by 106 · see citing works
Cho, J., Rameshwar, P., & Sadoshima, J. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.019109 · Cited by 68 · see citing works
Lal, H., Zhou, J., Ahmad, F., Zaka, R., Vagnozzi, R. J., DeCaul, M., Woodgett, J. R., Gao, E., & Force, T. L. (2011) · Circulation · doi:10.1161/circulationaha.111.050666 · Cited by 68 · see citing works
Growth control of multiple myeloma cells through inhibition of glycogen synthase kinase-3
Zhou, Y., Shahab Uddin, M. S., Zimmerman, T. M., Kang, J.-A., Ulaszek, J., & Wickrema, A. (2008) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428190802304966 · Cited by 51 · see citing works
Glycogen Synthase Kinase-3 regulates multiple myeloma cell growth and bortezomib-induced cell death
Piazza, F., Manni, S., Tubi, L. Q., Montini, B., Pavan, L., Colpo, A., Gnoato, M., Cabrelle, A., Adami, F., Zambello, R., et al. (2010) · BMC Cancer · doi:10.1186/1471-2407-10-526 · Cited by 43 · see citing works
Glycogen synthase kinase−3β inhibitors suppress leukemia cell growth
Song, E. Y., Palladinetti, P., Klamer, G., Ko, K., Lindeman, R., O'Brien, T. A., & Dolnikov, A. (2010) · Experimental Hematology · doi:10.1016/j.exphem.2010.06.001 · Cited by 40 · see citing works
LITHIUM IN ACUTE MYELOID LEUKÆMIA
Charron, D. J., Barrett, A. J., Faille, A., et al. (1977) · The Lancet · doi:10.1016/s0140-6736(77)91339-3 · Cited by 37 · see citing works
Zhang, N., Zhong, R., Yan, H., et al. (2010) · Chemical Biology & Drug Design · doi:10.1111/j.1747-0285.2010.01069.x · Cited by 27 · see citing works
Apoptosis Induced by Molecular Targeting Therapy in Hematological Malignancies
Adachi, S., Leoni, L. M., Carson, D. A., et al. (2003) · Acta Haematologica · doi:10.1159/000074490 · Cited by 18 · see citing works
Recent advances in the treatment of acute myeloid leukemia
Abdel-Wahab, O. I., & Levine, R. L. (2010) · F1000 Medicine Reports · doi:10.3410/m2-55 · Cited by 13 · see citing works
PREVENTION OF ANTIBLASTIC NEUTROPENIA WITH LITHIUM CARBONATE
Visca, U., Mensi, F., Spina, M. P., et al. (1979) · The Lancet · doi:10.1016/s0140-6736(79)91233-9 · Cited by 12 · see citing works
Stein, R. S., Vogler, W. R., & Lefante, J. J. (1984) · American Journal of Clinical Oncology · doi:10.1097/00000421-198408000-00014 · Cited by 10 · see citing works
Collado, S., Charron, D. J., & Degos, L. (1988) · Medical Oncology and Tumor Pharmacotherapy · doi:10.1007/bf02985446 · Cited by 3 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, Woodgett JR. Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activa- tion. Nature. 2000;406(6791):86-90.
- Lal H, et al. GSK-3alpha limits ischemic injury, car- diac rupture, post-myocardial infarction remodel- ing and death. Circulation. 2012;125(1):65-75.
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Wu, Y., Zhang, C., Liu, X., He, Z., Shan, B., Zeng, Q., Zhao, Q., Zhu, H., Liao, H., Cen, X., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22467-8 · Cited by 117 · see citing works
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Mishra, M., Thacker, G., Sharma, A., Singh, A. K., Upadhyay, V., Sanyal, S., Verma, S. P., Tripathi, A. K., Bhatt, M. L. B., & Trivedi, A. K. (2021) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-20-0268 · Cited by 30 · see citing works
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Amaral, B., Capacci, A., Anderson, T., Tezer, C., Bajrami, B., Lulla, M., Lucas, B., Chodaparambil, J. V., Marcotte, D., Kumar, P. R., et al. (2023) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.2c00476 · Cited by 22 · see citing works
GSK3α: An Important Paralog in Neurodegenerative Disorders and Cancer
Silva-García, O., Cortés-Vieyra, R., Mendoza-Ambrosio, F. N., Ramírez-Galicia, G., & Baizabal-Aguirre, V. M. (2020) · Biomolecules · doi:10.3390/biom10121683 · Cited by 17 · see citing works
- Authors
- Banerji, V., Frumm, S. M., Ross, K. N., Li, L. S., Schinzel, A. C., Hahn, C. K., Kakoza, R. M., Chow, K. T., Ross, L., Alexe, G., Tolliday, N., Inguilizian, H., Galinsky, I., Stone, R. M., DeAngelo, D. J., Roti, G., Aster, J. C., Hahn, W. C., Kung, A. L., & Stegmaier, K.
- Affiliations
- Boston Children's Hospital (US)
- Broad Institute (US)
- Dana-Farber Cancer Institute (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Corresponding author
- Stegmaier, Kimberly
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2012-03-01
- Volume
- 122
- Issue
- 3
- Pages
- 935-947
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3287215
- OpenAlex
- W1968904120
- Cited by
- 105
- References
- 49
- Citations by year
- 2025: 3 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 12 · 2020: 11 · 2019: 13 · 2018: 9 · 2017: 6 · 2016: 9 · 2015: 7 · 2014: 4 · 2013: 12 · 2012: 6
- FWCI
- 6.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- American Cancer Society
- Boston Foundation
- CancerCare Manitoba Foundation
- University of Manitoba
- Broad Institute
- Terry Fox Foundation
- National Cancer Institute (R01CA140292)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Keywords
- acute myeloid leukemia, glycogen synthase kinase-3α, GSK3β, shRNA screen, myeloid differentiation, apoptosis, cell proliferation, colony formation, antileukemic activity, drug target identification
- MeSH terms
- Cell Differentiation, Cell Survival, Humans, Neoplasms, Technology, Pharmaceutical, Leukemia, Myeloid, Acute, Gene Expression Regulation, Neoplastic, HL-60 Cells, U937 Cells, Gene Expression Profiling, Genomics, RNA Interference, Glycogen Synthase Kinase 3, Cell Proliferation
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