GSK3 Deficiencies in Hematopoietic Stem Cells Initiate Pre-neoplastic State that Is Predictive of Clinical Outcomes of Human Acute Leukemia

Guezguez, Borhane; Almakadi, Mohammed; Benoit, Yannick D.; Shapovalova, Zoya; Rahmig, Susann; Fiebig‐Comyn, Aline; Casado, Fanny L.; Tanasijevic, Borko; Bresolin, Silvia; Masetti, Riccardo; Doble, Bradley W.; Bhatia, Mickie

doi:10.1016/j.ccell.2015.11.012

Cited by 54 publications

(64 citation statements)

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“…Additional evidence for a direct role for GSK‐3 in myelodysplasia and leukemia comes from work with GSK‐3 inhibitors and Gsk3 knockouts in mice (Guezguez et al, ; Huang et al, ; McCubrey et al, ). Pharmacological inhibition or RNAi‐mediated knockdown of Gsk3 in mouse bone marrow causes a transient myeloproliferative state (Focosi, Azzara, Kast, Carulli, & Petrini, ; Huang et al, ), similar to Pten knockout in hematopoietic cells(Banerji et al, ; Yilmaz et al, ; J. Zhang et al, ), and complete knockout of Gsk3a and Gsk3b in mouse bone marrow causes a more severe myeloproliferative and dysplastic phenotype with marked increase in mature and immature granulocytes and dysplasia, as well as an increase in myeloid blasts that was suggestive of AML (Guezguez et al, ). The mechanism downstream of GSK‐3 appears to be in part through enhanced Wnt/ß‐catenin but additional downstream effectors of GSK‐3 likely contribute to this dramatic phenotype.…”

Section: Splicing Mutations In Cancermentioning

confidence: 99%

Glycogen synthase kinase‐3 and alternative splicing

Klein

2018

WIREs RNA

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Glycogen synthase kinase-3 (GSK-3) is a highly conserved negative regulator of receptor tyrosine kinase, cytokine, and Wnt signaling pathways. Stimulation of these pathways inhibits GSK-3 to modulate diverse downstream effectors that include transcription factors, nutrient sensors, glycogen synthesis, mitochondrial function, circadian rhythm, and cell fate. GSK-3 also regulates alternative splicing in response to T-cell receptor activation, and recent phosphoproteomic studies have revealed that multiple splicing factors and regulators of RNA biosynthesis are phosphorylated in a GSK-3-dependent manner. Furthermore, inhibition of GSK-3 alters the splicing of hundreds of mRNAs, indicating a broad role for GSK-3 in the regulation of RNA processing. GSK-3-regulated phosphoproteins include SF3B1, SRSF2, PSF, RBM8A, nucleophosmin 1 (NPM1), and PHF6, many of which are mutated in leukemia and myelodysplasia. As GSK-3 is inhibited by pathways that are pathologically activated in leukemia and loss of Gsk3 in hematopoietic cells causes a severe myelodysplastic neoplasm in mice, these findings strongly implicate GSK-3 as a critical regulator of mRNA processing in normal and malignant hematopoiesis. This article is categorized under: RNA Processing > Splicing Mechanisms RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

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Section: Splicing Mutations In Cancermentioning

confidence: 99%

Glycogen synthase kinase‐3 and alternative splicing

Klein

2018

WIREs RNA

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“…The evolutionarily conserved nutrient sensor mTORC1 antagonizes HSC function, as interventions that activate mTORC1, including loss of the negative regulators Pten [6], Gsk3 [7], and Tsc1 [8], lead to HSC proliferation followed by exhaustion and in some cases leukemogenesis [6, 9]. Developing a thorough understanding of mediators of mTORC1 signaling in this context will therefore be a critical step toward expansion of functional HSCs ex vivo .…”

Section: Introductionmentioning

confidence: 99%

Autophagy is a signature of a signaling network that maintains hematopoietic stem cells

Nguyen-McCarty

Klein

2017

PLoS ONE

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Hematopoietic stem cells (HSCs) are able to self-renew and to differentiate into all blood cells. HSCs reside in a low-perfusion niche and depend on local signals to survive and to maintain the capacity for self-renewal. HSCs removed from the niche are unable to survive without addition of hematopoietic cytokines and rapidly lose their ability to self-renew. We reported previously that inhibition of both GSK-3 and mTORC1 is essential to maintain long-term HSCs ex vivo. Although Wnt/β-catenin signaling downstream of GSK-3 is required for this response, the downstream effectors of mTORC1 remain undefined. We now report that HSCs express a pro-autophagic gene signature and accumulate LC3 puncta only when both mTORC1 and GSK-3 are inhibited, identifying autophagy as a signature for a signaling network that maintains HSCs ex vivo. In addition, these conditions sustain HSC repopulating function despite an increased rate of global translation. Together, these findings provide new insight into the relative contributions of various mTORC1 outputs toward the maintenance of HSC function and build upon the growing body of literature implicating autophagy and tightly controlled protein synthesis as important modulators of diverse stem cell populations.

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“…Knock-out of Gsk3 (DKO) in hematopoietic cells in mice causes a dramatic myeloproliferative and myelodysplastic disorder with features of AML (68). Whereas the signaling networks downstream of GSK-3 that mediate these neoplastic phenotypes are probably complex, disruption of splicing factor function through altered GSK-3-dependent phosphorylation, with subsequent disruption of splicing of mRNAs that encode hematopoietic regulators, could contribute to the progression of these neoplasms.…”

Section: Gsk-3 Phosphoproteomementioning

confidence: 99%

Phosphoproteomics reveals that glycogen synthase kinase-3 phosphorylates multiple splicing factors and is associated with alternative splicing

Shinde¹,

Sidoli²,

Kulej³

et al. 2017

Journal of Biological Chemistry

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Edited by Eric R. FearonGlycogen synthase kinase-3 (GSK-3) is a constitutively active, ubiquitously expressed protein kinase that regulates multiple signaling pathways. In vitro kinase assays and genetic and pharmacological manipulations of GSK-3 have identified more than 100 putative GSK-3 substrates in diverse cell types. Many more have been predicted on the basis of a recurrent GSK-3 consensus motif ((pS/pT)XXX(S/T)), but this prediction has not been tested by analyzing the GSK-3 phosphoproteome. Using stable isotope labeling of amino acids in culture (SILAC) and MS techniques to analyze the repertoire of GSK-3-dependent phosphorylation in mouse embryonic stem cells (ESCs), we found that ϳ2.4% of (pS/pT)XXX(S/T) sites are phosphorylated in a GSK-3-dependent manner. A comparison of WT and Gsk3a;Gsk3b knock-out (Gsk3 DKO) ESCs revealed prominent GSK-3-dependent phosphorylation of multiple splicing factors and regulators of RNA biosynthesis as well as proteins that regulate transcription, translation, and cell division. Gsk3 DKO reduced phosphorylation of the splicing factors RBM8A, SRSF9, and PSF as well as the nucleolar proteins NPM1 and PHF6, and recombinant GSK-3␤ phosphorylated these proteins in vitro. RNASeq of WT and Gsk3 DKO ESCs identified ϳ190 genes that are alternatively spliced in a GSK-3-dependent manner, supporting a broad role for GSK-3 in regulating alternative splicing. The MS data also identified posttranscriptional regulation of protein abundance by GSK-3, with ϳ47 proteins (1.4%) whose levels increased and ϳ78 (2.4%) whose levels decreased in the absence of GSK-3. This study provides the first unbiased analysis of the GSK-3 phosphoproteome and strong evidence that GSK-3 broadly regulates alternative splicing. Glycogen synthase kinase-3 (GSK-3)2 is a ubiquitously expressed, highly conserved serine/threonine kinase that plays a central role in multiple signaling pathways, most prominently as an antagonist of insulin/AKT and Wnt/␤-catenin signaling pathways (1). Unlike most protein kinases, GSK-3 is constitutively active and in general is inhibited by upstream signaling. GSK-3 was first identified as a protein kinase that phosphorylates and inhibits glycogen synthase, the rate-limiting enzyme in glycogen synthesis (2) and was later shown to antagonize canonical Wnt signaling (1). However, GSK-3 is now known to regulate a broad range of cellular processes, including cytoskeletal organization, circadian rhythm, cell growth and survival, immune responses, and developmental processes (1).In metazoans, GSK-3 is encoded by two similar genes, Gsk3a and Gsk3b, with 98% amino acid sequence identity in the catalytic domains of mammalian GSK-3␣ and GSK-3␤. The two genes are partially redundant, and mice with complete loss of Gsk3a are viable due to compensation by Gsk3b. However, Gsk3b loss-of-function mutations in mice are embryonic or neonatal lethal (3,4), and the Gsk3a;Gsk3b DKO is lethal in early embryogenesis (5, 6). Furthermore, DKO mouse ESCs maintain expression of pluripotency markers and are unab...

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GSK3 Deficiencies in Hematopoietic Stem Cells Initiate Pre-neoplastic State that Is Predictive of Clinical Outcomes of Human Acute Leukemia

Cited by 54 publications

References 100 publications

Glycogen synthase kinase‐3 and alternative splicing

Glycogen synthase kinase‐3 and alternative splicing

Autophagy is a signature of a signaling network that maintains hematopoietic stem cells

Phosphoproteomics reveals that glycogen synthase kinase-3 phosphorylates multiple splicing factors and is associated with alternative splicing

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