Regulation of Hematopoietic Stem Cell Fate and Malignancy
Abstract
1. Introduction
2. General Features of Hematopoietic Stem Cell (HSC) Aging
3. Regulation of HSC Fate during Aging
3.1. Hematopoietic Stem Cell (HSC) Quiescence Regulation
3.2. Regulation of HSC Self-Renewal and Differentiation
4. Regulation of HSC Fate and Malignancy
4.1. Phosphoinositide 3-Kinase (PI3K)
4.2. Protein Kinase B (PKB/AKT)
4.3. Mammalian Target of Rapamycin (mTOR)
4.4. Glycogen Synthase Kinase-3 (GSK-3)
4.5. p38 Mitogen-Activated Protein Kinase (p38)
4.6. Other Kinases and Their Inhibitors
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Jung, H.; Kim, D.O.; Byun, J.E.; Kim, W.S.; Kim, M.J.; Song, H.Y.; Kim, Y.K.; Kang, D.K.; Park, Y.J.; Kim, T.D.; et al. Thioredoxin-interacting protein regulates haematopoietic stem cell ageing and rejuvenation by inhibiting p38 kinase activity. Nat. Commun. 2016, 7, 13674. [Google Scholar] [CrossRef] [PubMed]
- Morrison, S.J.; Weissman, I.L. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1994, 1, 661–673. [Google Scholar] [CrossRef]
- Buitenhuis, M.; Verhagen, L.P.; van Deutekom, H.W.; Castor, A.; Verploegen, S.; Koenderman, L.; Jacobsen, S.E.; Coffer, P.J. Protein kinase B (c-akt) regulates hematopoietic lineage choice decisions during myelopoiesis. Blood 2008, 111, 112–121. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Janzen, V.; Forkert, R.; Fleming, H.E.; Saito, Y.; Waring, M.T.; Dombkowski, D.M.; Cheng, T.; DePinho, R.A.; Sharpless, N.E.; Scadden, D.T. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 2006, 443, 421–426. [Google Scholar] [CrossRef]
- Rigaud, S.; Sauer, K. IP3 3-kinase B prevents bone marrow failure. Oncotarget 2015, 6, 15706–15707. [Google Scholar] [CrossRef] [PubMed]
- Lee, D.H.; Kim, T.S.; Lee, D.; Lim, D.S. Mammalian sterile 20 kinase 1 and 2 are important regulators of hematopoietic stem cells in stress condition. Sci. Rep. 2018, 8, 942. [Google Scholar] [CrossRef] [PubMed]
- Rossi, D.J.; Seita, J.; Czechowicz, A.; Bhattacharya, D.; Bryder, D.; Weissman, I.L. Hematopoietic stem cell quiescence attenuates DNA damage response and permits DNA damage accumulation during aging. Cell Cycle 2007, 6, 2371–2376. [Google Scholar] [CrossRef]
- Kirschner, K.; Chandra, T.; Kiselev, V.; Flores-Santa Cruz, D.; Macaulay, I.C.; Park, H.J.; Li, J.; Kent, D.G.; Kumar, R.; Pask, D.C.; et al. Proliferation drives aging-related functional decline in a subpopulation of the hematopoietic stem cell compartment. Cell Rep. 2017, 19, 1503–1511. [Google Scholar] [CrossRef]
- De Haan, G.; Lazare, S.S. Aging of hematopoietic stem cells. Blood 2018, 131, 479–487. [Google Scholar] [CrossRef]
- Beerman, I.; Seita, J.; Inlay, M.A.; Weissman, I.L.; Rossi, D.J. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell 2014, 15, 37–50. [Google Scholar] [CrossRef] [PubMed]
- Lee, J.; Yoon, S.R.; Choi, I.; Jung, H. Causes and mechanisms of hematopoietic stem cell aging. Int. J. Mol. Sci. 2019, 20, 1272. [Google Scholar] [CrossRef]
- Rossi, D.J.; Bryder, D.; Zahn, J.M.; Ahlenius, H.; Sonu, R.; Wagers, A.J.; Weissman, I.L. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc. Natl. Acad. Sci. USA 2005, 102, 9194–9199. [Google Scholar] [CrossRef] [PubMed]
- Kuranda, K.; Vargaftig, J.; de la Rochere, P.; Dosquet, C.; Charron, D.; Bardin, F.; Tonnelle, C.; Bonnet, D.; Goodhardt, M. Age-related changes in human hematopoietic stem/progenitor cells. Aging Cell 2011, 10, 542–546. [Google Scholar] [CrossRef] [PubMed]
- Dykstra, B.; Olthof, S.; Schreuder, J.; Ritsema, M.; de Haan, G. Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells. J. Exp. Med. 2011, 208, 2691–2703. [Google Scholar] [CrossRef] [PubMed]
- Li, X.; Zeng, X.; Xu, Y.; Wang, B.; Zhao, Y.; Lai, X.; Qian, P.; Huang, H. Mechanisms and rejuvenation strategies for aged hematopoietic stem cells. J. Hematol. Oncol. 2020, 13, 31. [Google Scholar] [CrossRef] [PubMed]
- Kim, M.; Moon, H.B.; Spangrude, G.J. Major age-related changes of mouse hematopoietic stem/progenitor cells. Ann. N. Y. Acad. Sci. 2003, 996, 195–208. [Google Scholar] [CrossRef] [PubMed]
- Snoeck, H.W. Aging of the hematopoietic system. Curr. Opin. Hematol. 2013, 20, 355–361. [Google Scholar] [CrossRef]
- Beerman, I.; Bhattacharya, D.; Zandi, S.; Sigvardsson, M.; Weissman, I.L.; Bryder, D.; Rossi, D.J. Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc. Natl. Acad. Sci. USA 2010, 107, 5465–5470. [Google Scholar] [CrossRef]
- Cho, R.H.; Sieburg, H.B.; Muller-Sieburg, C.E. A new mechanism for the aging of hematopoietic stem cells: Aging changes the clonal composition of the stem cell compartment but not individual stem cells. Blood 2008, 111, 5553–5561. [Google Scholar] [CrossRef]
- Yamamoto, R.; Wilkinson, A.C.; Ooehara, J.; Lan, X.; Lai, C.Y.; Nakauchi, Y.; Pritchard, J.K.; Nakauchi, H. Large-scale clonal analysis resolves aging of the mouse hematopoietic stem cell compartment. Cell Stem Cell 2018, 22, 600–607 e4. [Google Scholar] [CrossRef]
- Rube, C.E.; Fricke, A.; Widmann, T.A.; Furst, T.; Madry, H.; Pfreundschuh, M.; Rube, C. Accumulation of DNA damage in hematopoietic stem and progenitor cells during human aging. PLoS ONE 2011, 6, e17487. [Google Scholar] [CrossRef] [PubMed]
- Bernitz, J.M.; Kim, H.S.; MacArthur, B.; Sieburg, H.; Moore, K. Hematopoietic stem cells count and remember self-renewal divisions. Cell 2016, 167, 1296–1309. [Google Scholar] [CrossRef] [PubMed]
- Cho, I.J.; Lui, P.P.; Obajdin, J.; Riccio, F.; Stroukov, W.; Willis, T.L.; Spagnoli, F.; Watt, F.M. Mechanisms, hallmarks, and implications of stem cell quiescence. Stem Cell Rep. 2019, 12, 1190–1200. [Google Scholar] [CrossRef] [PubMed]
- Tumpel, S.; Rudolph, K.L. Quiescence: Good and bad of stem cell aging. Trends Cell Biol. 2019, 29, 672–685. [Google Scholar] [CrossRef]
- Li, J. Quiescence regulators for hematopoietic stem cell. Exp. Hematol. 2011, 39, 511–520. [Google Scholar] [CrossRef]
- Venezia, T.A.; Merchant, A.A.; Ramos, C.A.; Whitehouse, N.L.; Young, A.S.; Shaw, C.A.; Goodell, M.A. Molecular signatures of proliferation and quiescence in hematopoietic stem cells. PLoS Biol. 2004, 2, e301. [Google Scholar] [CrossRef] [PubMed]
- Nakamura-Ishizu, A.; Takizawa, H.; Suda, T. The analysis, roles and regulation of quiescence in hematopoietic stem cells. Development 2014, 141, 4656–4666. [Google Scholar] [CrossRef]
- Walter, D.; Lier, A.; Geiselhart, A.; Thalheimer, F.B.; Huntscha, S.; Sobotta, M.C.; Moehrle, B.; Brocks, D.; Bayindir, I.; Kaschutnig, P.; et al. Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells. Nature 2015, 520, 549–552. [Google Scholar] [CrossRef]
- Visnjic, D.; Kalajzic, Z.; Rowe, D.W.; Katavic, V.; Lorenzo, J.; Aguila, H.L. Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood 2004, 103, 3258–3264. [Google Scholar] [CrossRef]
- Arai, F.; Hirao, A.; Ohmura, M.; Sato, H.; Matsuoka, S.; Takubo, K.; Ito, K.; Koh, G.Y.; Suda, T. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 2004, 118, 149–161. [Google Scholar] [CrossRef]
- Yoshihara, H.; Arai, F.; Hosokawa, K.; Hagiwara, T.; Takubo, K.; Nakamura, Y.; Gomei, Y.; Iwasaki, H.; Matsuoka, S.; Miyamoto, K.; et al. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell 2007, 1, 685–697. [Google Scholar] [CrossRef]
- Greenbaum, A.; Hsu, Y.M.; Day, R.B.; Schuettpelz, L.G.; Christopher, M.J.; Borgerding, J.N.; Nagasawa, T.; Link, D.C. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 2013, 495, 227–230. [Google Scholar] [CrossRef] [PubMed]
- Ding, L.; Morrison, S.J. Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 2013, 495, 231–235. [Google Scholar] [CrossRef] [PubMed]
- Wang, Z.; Ema, H. Mechanisms of self-renewal in hematopoietic stem cells. Int. J. Hematol. 2016, 103, 498–509. [Google Scholar] [CrossRef]
- Bowers, M.; Zhang, B.; Ho, Y.; Agarwal, P.; Chen, C.C.; Bhatia, R. Osteoblast ablation reduces normal long-term hematopoietic stem cell self-renewal but accelerates leukemia development. Blood 2015, 125, 2678–2688. [Google Scholar] [CrossRef] [PubMed]
- Parmar, K.; Mauch, P.; Vergilio, J.A.; Sackstein, R.; Down, J.D. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc. Natl. Acad. Sci. USA 2007, 104, 5431–5436. [Google Scholar] [CrossRef]
- Trimarchi, J.M.; Lees, J.A. Sibling rivalry in the E2F family. Nat. Rev. Mol. Cell Biol. 2002, 3, 11–20. [Google Scholar] [CrossRef]
- Viatour, P.; Somervaille, T.C.; Venkatasubrahmanyam, S.; Kogan, S.; McLaughlin, M.E.; Weissman, I.L.; Butte, A.J.; Passegue, E.; Sage, J. Hematopoietic stem cell quiescence is maintained by compound contributions of the retinoblastoma gene family. Cell Stem Cell 2008, 3, 416–428. [Google Scholar] [CrossRef]
- Spencer, S.L.; Cappell, S.D.; Tsai, F.C.; Overton, K.W.; Wang, C.L.; Meyer, T. The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit. Cell 2013, 155, 369–383. [Google Scholar] [CrossRef]
- Takubo, K.; Goda, N.; Yamada, W.; Iriuchishima, H.; Ikeda, E.; Kubota, Y.; Shima, H.; Johnson, R.S.; Hirao, A.; Suematsu, M.; et al. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell 2010, 7, 391–402. [Google Scholar] [CrossRef]
- Takubo, K.; Nagamatsu, G.; Kobayashi, C.I.; Nakamura-Ishizu, A.; Kobayashi, H.; Ikeda, E.; Goda, N.; Rahimi, Y.; Johnson, R.S.; Soga, T.; et al. Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell 2013, 12, 49–61. [Google Scholar] [CrossRef] [PubMed]
- Lu, Z.; Hong, C.C.; Kong, G.; Assumpcao, A.; Ong, I.M.; Bresnick, E.H.; Zhang, J.; Pan, X. Polycomb group protein YY1 is an essential regulator of hematopoietic stem cell quiescence. Cell Rep. 2018, 22, 1545–1559. [Google Scholar] [CrossRef] [PubMed]
- Ho, T.T.; Warr, M.R.; Adelman, E.R.; Lansinger, O.M.; Flach, J.; Verovskaya, E.V.; Figueroa, M.E.; Passegue, E. Autophagy maintains the metabolism and function of young and old stem cells. Nature 2017, 543, 205–210. [Google Scholar] [CrossRef] [PubMed]
- Dykstra, B.; de Haan, G. Hematopoietic stem cell aging and self-renewal. Cell Tissue Res. 2008, 331, 91–101. [Google Scholar] [CrossRef]
- Seita, J.; Weissman, I.L. Hematopoietic stem cell: Self-renewal versus differentiation. Wiley Interdiscip. Rev. Syst. Biol. Med. 2010, 2, 640–653. [Google Scholar] [CrossRef]
- Morrison, S.J.; Wandycz, A.M.; Akashi, K.; Globerson, A.; Weissman, I.L. The aging of hematopoietic stem cells. Nat. Med. 1996, 2, 1011–1016. [Google Scholar] [CrossRef]
- Nygren, J.M.; Bryder, D.; Jacobsen, S.E. Prolonged cell cycle transit is a defining and developmentally conserved hemopoietic stem cell property. J. Immunol. 2006, 177, 201–208. [Google Scholar] [CrossRef] [PubMed]
- Bowie, M.B.; McKnight, K.D.; Kent, D.G.; McCaffrey, L.; Hoodless, P.A.; Eaves, C.J. Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect. J. Clin. Investig. 2006, 116, 2808–2816. [Google Scholar] [CrossRef] [PubMed]
- Nygren, J.M.; Bryder, D. A novel assay to trace proliferation history in vivo reveals that enhanced divisional kinetics accompany loss of hematopoietic stem cell self-renewal. PLoS ONE 2008, 3, e3710. [Google Scholar] [CrossRef] [PubMed]
- Omatsu, Y.; Seike, M.; Sugiyama, T.; Kume, T.; Nagasawa, T. Foxc1 is a critical regulator of haematopoietic stem/progenitor cell niche formation. Nature 2014, 508, 536–540. [Google Scholar] [CrossRef] [PubMed]
- Zhou, B.O.; Yue, R.; Murphy, M.M.; Peyer, J.G.; Morrison, S.J. Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell 2014, 15, 154–168. [Google Scholar] [CrossRef] [PubMed]
- Nie, Y.; Han, Y.C.; Zou, Y.R. CXCR4 is required for the quiescence of primitive hematopoietic cells. J. Exp. Med. 2008, 205, 777–783. [Google Scholar] [CrossRef] [PubMed]
- Thoren, L.A.; Liuba, K.; Bryder, D.; Nygren, J.M.; Jensen, C.T.; Qian, H.; Antonchuk, J.; Jacobsen, S.E. Kit regulates maintenance of quiescent hematopoietic stem cells. J. Immunol. 2008, 180, 2045–2053. [Google Scholar] [CrossRef] [PubMed]
- Larsson, J.; Blank, U.; Helgadottir, H.; Bjornsson, J.M.; Ehinger, M.; Goumans, M.J.; Fan, X.; Leveen, P.; Karlsson, S. TGF-beta signaling-deficient hematopoietic stem cells have normal self-renewal and regenerative ability in vivo despite increased proliferative capacity in vitro. Blood 2003, 102, 3129–3135. [Google Scholar] [CrossRef]
- Yamazaki, S.; Ema, H.; Karlsson, G.; Yamaguchi, T.; Miyoshi, H.; Shioda, S.; Taketo, M.M.; Karlsson, S.; Iwama, A.; Nakauchi, H. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 2011, 147, 1146–1158. [Google Scholar] [CrossRef] [PubMed]
- Karlsson, G.; Blank, U.; Moody, J.L.; Ehinger, M.; Singbrant, S.; Deng, C.X.; Karlsson, S. Smad4 is critical for self-renewal of hematopoietic stem cells. J. Exp. Med. 2007, 204, 467–474. [Google Scholar] [CrossRef]
- Essers, M.A.; Offner, S.; Blanco-Bose, W.E.; Waibler, Z.; Kalinke, U.; Duchosal, M.A.; Trumpp, A. IFNalpha activates dormant haematopoietic stem cells in vivo. Nature 2009, 458, 904–908. [Google Scholar] [CrossRef]
- Franceschi, C.; Campisi, J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med. Sci. 2014, 69 (Suppl. 1), S4–S9. [Google Scholar] [CrossRef] [PubMed]
- Baldridge, M.T.; King, K.Y.; Goodell, M.A. Inflammatory signals regulate hematopoietic stem cells. Trends Immunol. 2011, 32, 57–65. [Google Scholar] [CrossRef]
- Pronk, C.J.; Veiby, O.P.; Bryder, D.; Jacobsen, S.E. Tumor necrosis factor restricts hematopoietic stem cell activity in mice: Involvement of two distinct receptors. J. Exp. Med. 2011, 208, 1563–1570. [Google Scholar] [CrossRef]
- Lee, J.; Cho, Y.S.; Jung, H.; Choi, I. Pharmacological regulation of oxidative stress in stem cells. Oxid. Med. Cell Longev. 2018, 2018, 4081890. [Google Scholar] [CrossRef] [PubMed]
- Jang, Y.Y.; Sharkis, S.J. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood 2007, 110, 3056–3063. [Google Scholar] [CrossRef]
- Staber, P.B.; Zhang, P.; Ye, M.; Welner, R.S.; Nombela-Arrieta, C.; Bach, C.; Kerenyi, M.; Bartholdy, B.A.; Zhang, H.; Alberich-Jorda, M.; et al. Sustained PU.1 levels balance cell-cycle regulators to prevent exhaustion of adult hematopoietic stem cells. Mol. Cell 2013, 49, 934–946. [Google Scholar] [CrossRef] [PubMed]
- Miyamoto, K.; Araki, K.Y.; Naka, K.; Arai, F.; Takubo, K.; Yamazaki, S.; Matsuoka, S.; Miyamoto, T.; Ito, K.; Ohmura, M.; et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 2007, 1, 101–112. [Google Scholar] [CrossRef]
- Jung, H.; Kim, M.J.; Kim, D.O.; Kim, W.S.; Yoon, S.J.; Park, Y.J.; Yoon, S.R.; Kim, T.D.; Suh, H.W.; Yun, S.; et al. TXNIP maintains the hematopoietic cell pool by switching the function of p53 under oxidative stress. Cell Metab. 2013, 18, 75–85. [Google Scholar] [CrossRef]
- Chen, Z.; Amro, E.M.; Becker, F.; Holzer, M.; Rasa, S.M.M.; Njeru, S.N.; Han, B.; Di Sanzo, S.; Chen, Y.; Tang, D.; et al. Cohesin-mediated NF-kappaB signaling limits hematopoietic stem cell self-renewal in aging and inflammation. J. Exp. Med. 2019, 216, 152–175. [Google Scholar] [CrossRef]
- Yu, W.M.; Liu, X.; Shen, J.; Jovanovic, O.; Pohl, E.E.; Gerson, S.L.; Finkel, T.; Broxmeyer, H.E.; Qu, C.K. Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation. Cell Stem Cell 2013, 12, 62–74. [Google Scholar] [CrossRef] [PubMed]
- Sun, D.; Luo, M.; Jeong, M.; Rodriguez, B.; Xia, Z.; Hannah, R.; Wang, H.; Le, T.; Faull, K.F.; Chen, R.; et al. Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell 2014, 14, 673–688. [Google Scholar] [CrossRef]
- Florian, M.C.; Dorr, K.; Niebel, A.; Daria, D.; Schrezenmeier, H.; Rojewski, M.; Filippi, M.D.; Hasenberg, A.; Gunzer, M.; Scharffetter-Kochanek, K.; et al. Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell 2012, 10, 520–530. [Google Scholar] [CrossRef]
- Manning, G.; Whyte, D.B.; Martinez, R.; Hunter, T.; Sudarsanam, S. The protein kinase complement of the human genome. Science 2002, 298, 1912–1934. [Google Scholar] [CrossRef]
- Endicott, J.A.; Noble, M.E.; Johnson, L.N. The structural basis for control of eukaryotic protein kinases. Annu. Rev. Biochem. 2012, 81, 587–613. [Google Scholar] [CrossRef]
- Hu, T.; Li, C.; Wang, L.; Zhang, Y.; Peng, L.; Cheng, H.; Chu, Y.; Wang, W.; Ema, H.; Gao, Y.; et al. PDK1 plays a vital role on hematopoietic stem cell function. Sci. Rep. 2017, 7, 4943. [Google Scholar] [CrossRef]
- Huang, J.; Zhang, Y.; Bersenev, A.; O’Brien, W.T.; Tong, W.; Emerson, S.G.; Klein, P.S. Pivotal role for glycogen synthase kinase-3 in hematopoietic stem cell homeostasis in mice. J. Clin. Investig. 2009, 119, 3519–3529. [Google Scholar] [CrossRef]
- Kleppe, M.; Spitzer, M.H.; Li, S.; Hill, C.E.; Dong, L.; Papalexi, E.; De Groote, S.; Bowman, R.L.; Keller, M.; Koppikar, P.; et al. Jak1 integrates cytokine sensing to regulate hematopoietic stem cell function and stress hematopoiesis. Cell Stem Cell 2017, 21, 489–501. [Google Scholar] [CrossRef]
- Guo, F.; Zhang, S.; Grogg, M.; Cancelas, J.A.; Varney, M.E.; Starczynowski, D.T.; Du, W.; Yang, J.Q.; Liu, W.; Thomas, G.; et al. Mouse gene targeting reveals an essential role of mTOR in hematopoietic stem cell engraftment and hematopoiesis. Haematologica 2013, 98, 1353–1358. [Google Scholar] [CrossRef]
- Polak, R.; Buitenhuis, M. The PI3K/PKB signaling module as key regulator of hematopoiesis: Implications for therapeutic strategies in leukemia. Blood 2012, 119, 911–923. [Google Scholar] [CrossRef] [PubMed]
- Vanhaesebroeck, B.; Guillermet-Guibert, J.; Graupera, M.; Bilanges, B. The emerging mechanisms of isoform-specific PI3K signalling. Nat. Rev. Mol. Cell Biol. 2010, 11, 329–341. [Google Scholar] [CrossRef] [PubMed]
- Gopal, A.K.; Kahl, B.S.; de Vos, S.; Wagner-Johnston, N.D.; Schuster, S.J.; Jurczak, W.J.; Flinn, I.W.; Flowers, C.R.; Martin, P.; Viardot, A.; et al. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N. Engl. J. Med. 2014, 370, 1008–1018. [Google Scholar] [CrossRef] [PubMed]
- Elich, M.; Sauer, K. Regulation of hematopoietic cell development and function through phosphoinositides. Front. Immunol. 2018, 9, 931. [Google Scholar] [CrossRef]
- Siegemund, S.; Rigaud, S.; Conche, C.; Broaten, B.; Schaffer, L.; Westernberg, L.; Head, S.R.; Sauer, K. IP3 3-kinase B controls hematopoietic stem cell homeostasis and prevents lethal hematopoietic failure in mice. Blood 2015, 125, 2786–2797. [Google Scholar] [CrossRef]
- Haneline, L.S.; White, H.; Yang, F.C.; Chen, S.; Orschell, C.; Kapur, R.; Ingram, D.A. Genetic reduction of class IA PI-3 kinase activity alters fetal hematopoiesis and competitive repopulating ability of hematopoietic stem cells in vivo. Blood 2006, 107, 1375–1382. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Buitenhuis, M.; Coffer, P.J. The role of the PI3K-PKB signaling module in regulation of hematopoiesis. Cell Cycle 2009, 8, 560–566. [Google Scholar] [CrossRef] [PubMed]
- Okkenhaug, K.; Fruman, D.A. PI3Ks in lymphocyte signaling and development. Curr. Top. Microbiol. Immunol. 2010, 346, 57–85. [Google Scholar] [PubMed]
- Fruman, D.A.; Mauvais-Jarvis, F.; Pollard, D.A.; Yballe, C.M.; Brazil, D.; Bronson, R.T.; Kahn, C.R.; Cantley, L.C. Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85 alpha. Nat. Genet. 2000, 26, 379–382. [Google Scholar] [CrossRef] [PubMed]
- Okkenhaug, K.; Bilancio, A.; Farjot, G.; Priddle, H.; Sancho, S.; Peskett, E.; Pearce, W.; Meek, S.E.; Salpekar, A.; Waterfield, M.D.; et al. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 2002, 297, 1031–1034. [Google Scholar] [CrossRef] [PubMed]
- Liu, L.; Zhu, S.; Gong, Z.; Low, B.C. K-ras/PI3K-Akt signaling is essential for zebrafish hematopoiesis and angiogenesis. PLoS ONE 2008, 3, e2850. [Google Scholar] [CrossRef]
- Maira, S.M.; Stauffer, F.; Brueggen, J.; Furet, P.; Schnell, C.; Fritsch, C.; Brachmann, S.; Chene, P.; De Pover, A.; Schoemaker, K.; et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol. Cancer Ther. 2008, 7, 1851–1863. [Google Scholar] [CrossRef]
- Perry, J.M.; He, X.C.; Sugimura, R.; Grindley, J.C.; Haug, J.S.; Ding, S.; Li, L. Cooperation between both Wnt/{beta}ccc-catenin and PTEN/PI3K/Akt signaling promotes primitive hematopoietic stem cell self-renewal and expansion. Genes Dev. 2011, 25, 1928–1942. [Google Scholar] [CrossRef]
- Burgering, B.M.; Coffer, P.J. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 1995, 376, 599–602. [Google Scholar] [CrossRef]
- Manning, B.D.; Cantley, L.C. AKT/PKB signaling: Navigating downstream. Cell 2007, 129, 1261–1274. [Google Scholar] [CrossRef]
- Chen, W.S.; Xu, P.Z.; Gottlob, K.; Chen, M.L.; Sokol, K.; Shiyanova, T.; Roninson, I.; Weng, W.; Suzuki, R.; Tobe, K.; et al. Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev. 2001, 15, 2203–2208. [Google Scholar] [CrossRef] [PubMed]
- Cho, H.; Mu, J.; Kim, J.K.; Thorvaldsen, J.L.; Chu, Q.; Crenshaw, E.B., 3rd; Kaestner, K.H.; Bartolomei, M.S.; Shulman, G.I.; Birnbaum, M.J. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 2001, 292, 1728–1731. [Google Scholar] [CrossRef] [PubMed]
- Cho, H.; Thorvaldsen, J.L.; Chu, Q.; Feng, F.; Birnbaum, M.J. Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J. Biol. Chem. 2001, 276, 38349–38352. [Google Scholar] [CrossRef] [PubMed]
- Juntilla, M.M.; Wofford, J.A.; Birnbaum, M.J.; Rathmell, J.C.; Koretzky, G.A. Akt1 and Akt2 are required for alphabeta thymocyte survival and differentiation. Proc. Natl. Acad. Sci. USA 2007, 104, 12105–12110. [Google Scholar] [CrossRef] [PubMed]
- Tschopp, O.; Yang, Z.Z.; Brodbeck, D.; Dummler, B.A.; Hemmings-Mieszczak, M.; Watanabe, T.; Michaelis, T.; Frahm, J.; Hemmings, B.A. Essential role of protein kinase B gamma (PKB gamma/Akt3) in postnatal brain development but not in glucose homeostasis. Development 2005, 132, 2943–2954. [Google Scholar] [CrossRef] [PubMed]
- Juntilla, M.M.; Patil, V.D.; Calamito, M.; Joshi, R.P.; Birnbaum, M.J.; Koretzky, G.A. AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species. Blood 2010, 115, 4030–4038. [Google Scholar] [CrossRef] [PubMed]
- Garofalo, R.S.; Orena, S.J.; Rafidi, K.; Torchia, A.J.; Stock, J.L.; Hildebrandt, A.L.; Coskran, T.; Black, S.C.; Brees, D.J.; Wicks, J.R.; et al. Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J. Clin. Investig. 2003, 112, 197–208. [Google Scholar] [CrossRef]
- Kharas, M.G.; Okabe, R.; Ganis, J.J.; Gozo, M.; Khandan, T.; Paktinat, M.; Gilliland, D.G.; Gritsman, K. Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice. Blood 2010, 115, 1406–1415. [Google Scholar] [CrossRef]
- Lin, K.K.; Rossi, L.; Boles, N.C.; Hall, B.E.; George, T.C.; Goodell, M.A. CD81 is essential for the re-entry of hematopoietic stem cells to quiescence following stress-induced proliferation via deactivation of the Akt pathway. PLoS Biol. 2011, 9, e1001148. [Google Scholar] [CrossRef]
- Chiarini, F.; Del Sole, M.; Mongiorgi, S.; Gaboardi, G.C.; Cappellini, A.; Mantovani, I.; Follo, M.Y.; McCubrey, J.A.; Martelli, A.M. The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism. Leukemia 2008, 22, 1106–1116. [Google Scholar] [CrossRef]
- Papa, V.; Tazzari, P.L.; Chiarini, F.; Cappellini, A.; Ricci, F.; Billi, A.M.; Evangelisti, C.; Ottaviani, E.; Martinelli, G.; Testoni, N.; et al. Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells. Leukemia 2008, 22, 147–160. [Google Scholar] [CrossRef] [PubMed][Green Version]
- She, Q.B.; Chandarlapaty, S.; Ye, Q.; Lobo, J.; Haskell, K.M.; Leander, K.R.; DeFeo-Jones, D.; Huber, H.E.; Rosen, N. Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling. PLoS ONE 2008, 3, e3065. [Google Scholar] [CrossRef] [PubMed]
- Chen, S.; Gao, R.; Kobayashi, M.; Yu, H.; Yao, C.; Kapur, R.; Yoder, M.C.; Liu, Y. Pharmacological inhibition of AKT activity in human CD34(+) cells enhances their ability to engraft immunodeficient mice. Exp. Hematol. 2017, 45, 74–84. [Google Scholar] [CrossRef] [PubMed]
- Tabellini, G.; Tazzari, P.L.; Bortul, R.; Billi, A.M.; Conte, R.; Manzoli, L.; Cocco, L.; Martelli, A.M. Novel 2′-substituted, 3′-deoxy-phosphatidyl-myo-inositol analogues reduce drug resistance in human leukaemia cell lines with an activated phosphoinositide 3-kinase/Akt pathway. Br. J. Haematol. 2004, 126, 574–582. [Google Scholar] [CrossRef]
- Knapp, D.J.; Hammond, C.A.; Aghaeepour, N.; Miller, P.H.; Pellacani, D.; Beer, P.A.; Sachs, K.; Qiao, W.; Wang, W.; Humphries, R.K.; et al. Distinct signaling programs control human hematopoietic stem cell survival and proliferation. Blood 2017, 129, 307–318. [Google Scholar] [CrossRef]
- Evangelisti, C.; Ricci, F.; Tazzari, P.; Chiarini, F.; Battistelli, M.; Falcieri, E.; Ognibene, A.; Pagliaro, P.; Cocco, L.; McCubrey, J.A.; et al. Preclinical testing of the Akt inhibitor triciribine in T-cell acute lymphoblastic leukemia. J. Cell. Physiol. 2011, 226, 822–831. [Google Scholar] [CrossRef]
- Gan, B.; DePinho, R.A. mTORC1 signaling governs hematopoietic stem cell quiescence. Cell Cycle 2009, 8, 1003–1006. [Google Scholar] [CrossRef]
- Foster, K.G.; Fingar, D.C. Mammalian target of rapamycin (mTOR): Conducting the cellular signaling symphony. J. Biol. Chem. 2010, 285, 14071–14077. [Google Scholar] [CrossRef]
- Wullschleger, S.; Loewith, R.; Hall, M.N. TOR signaling in growth and metabolism. Cell 2006, 124, 471–484. [Google Scholar] [CrossRef]
- Proud, C.G. The multifaceted role of mTOR in cellular stress responses. DNA Repair 2004, 3, 927–934. [Google Scholar] [CrossRef]
- Martelli, A.M.; Evangelisti, C.; Chiarini, F.; Grimaldi, C.; Cappellini, A.; Ognibene, A.; McCubrey, J.A. The emerging role of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in normal myelopoiesis and leukemogenesis. Biochim. Biophys. Acta 2010, 1803, 991–1002. [Google Scholar] [CrossRef] [PubMed]
- Zhang, J.; Grindley, J.C.; Yin, T.; Jayasinghe, S.; He, X.C.; Ross, J.T.; Haug, J.S.; Rupp, D.; Porter-Westpfahl, K.S.; Wiedemann, L.M.; et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 2006, 441, 518–522. [Google Scholar] [CrossRef] [PubMed]
- Chen, C.; Liu, Y.; Liu, R.; Ikenoue, T.; Guan, K.L.; Liu, Y.; Zheng, P. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J. Exp. Med. 2008, 205, 2397–2408. [Google Scholar] [CrossRef]
- Gangloff, Y.G.; Mueller, M.; Dann, S.G.; Svoboda, P.; Sticker, M.; Spetz, J.F.; Um, S.H.; Brown, E.J.; Cereghini, S.; Thomas, G.; et al. Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development. Mol. Cell. Biol. 2004, 24, 9508–9516. [Google Scholar] [CrossRef] [PubMed]
- Delgoffe, G.M.; Kole, T.P.; Zheng, Y.; Zarek, P.E.; Matthews, K.L.; Xiao, B.; Worley, P.F.; Kozma, S.C.; Powell, J.D. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 2009, 30, 832–844. [Google Scholar] [CrossRef]
- Yilmaz, O.H.; Valdez, R.; Theisen, B.K.; Guo, W.; Ferguson, D.O.; Wu, H.; Morrison, S.J. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006, 441, 475–482. [Google Scholar] [CrossRef]
- Yee, K.W.; Zeng, Z.; Konopleva, M.; Verstovsek, S.; Ravandi, F.; Ferrajoli, A.; Thomas, D.; Wierda, W.; Apostolidou, E.; Albitar, M.; et al. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin. Cancer Res. 2006, 12, 5165–5173. [Google Scholar] [CrossRef]
- Decker, T.; Sandherr, M.; Goetze, K.; Oelsner, M.; Ringshausen, I.; Peschel, C. A pilot trial of the mTOR (mammalian target of rapamycin) inhibitor RAD001 in patients with advanced B-CLL. Ann. Hematol. 2009, 88, 221–227. [Google Scholar] [CrossRef]
- Choi, J.; Chen, J.; Schreiber, S.L.; Clardy, J. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 1996, 273, 239–242. [Google Scholar] [CrossRef]
- Janes, M.R.; Limon, J.J.; So, L.; Chen, J.; Lim, R.J.; Chavez, M.A.; Vu, C.; Lilly, M.B.; Mallya, S.; Ong, S.T.; et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nature Med. 2010, 16, 205–213. [Google Scholar] [CrossRef]
- Evangelisti, C.; Ricci, F.; Tazzari, P.; Tabellini, G.; Battistelli, M.; Falcieri, E.; Chiarini, F.; Bortul, R.; Melchionda, F.; Pagliaro, P.; et al. Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia. Leukemia 2011, 25, 781–791. [Google Scholar] [CrossRef] [PubMed]
- Yang, A.; Xiao, X.; Zhao, M.; LaRue, A.C.; Schulte, B.A.; Wang, G.Y. Differential reponses of hematopoietic stem and progenitor cells to mTOR inhibition. Stem Cells Int. 2015, 2015, 561404. [Google Scholar] [CrossRef] [PubMed]
- Frame, S.; Cohen, P. GSK3 takes centre stage more than 20 years after its discovery. Biochem. J. 2001, 359 Pt 1, 1–16. [Google Scholar] [CrossRef]
- Cohen, P. The hormonal control of glycogen metabolism in mammalian muscle by multivalent phosphorylation. Biochem. Soc. Trans. 1979, 7, 459–480. [Google Scholar] [CrossRef] [PubMed]
- Patel, S.; Woodgett, J. Glycogen synthase kinase-3 and cancer: Good cop, bad cop? Cancer Cell 2008, 14, 351–353. [Google Scholar] [CrossRef] [PubMed]
- 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.; et al. The intersection of genetic and chemical genomic screens identifies GSK-3alpha as a target in human acute myeloid leukemia. J. Clin. Investig. 2012, 122, 935–947. [Google Scholar] [CrossRef]
- McCubrey, J.A.; Steelman, L.S.; Bertrand, F.E.; Davis, N.M.; Abrams, S.L.; Montalto, G.; D’Assoro, A.B.; Libra, M.; Nicoletti, F.; Maestro, R.; et al. Multifaceted roles of GSK-3 and Wnt/beta-catenin in hematopoiesis and leukemogenesis: Opportunities for therapeutic intervention. Leukemia 2014, 28, 15–33. [Google Scholar] [CrossRef]
- Trowbridge, J.J.; Xenocostas, A.; Moon, R.T.; Bhatia, M. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nat. Med. 2006, 12, 89–98. [Google Scholar] [CrossRef]
- Purton, L.E.; Scadden, D.T. Limiting factors in murine hematopoietic stem cell assays. Cell Stem Cell 2007, 1, 263–270. [Google Scholar] [CrossRef]
- Kiel, M.J.; Yilmaz, O.H.; Iwashita, T.; Yilmaz, O.H.; Terhorst, C.; Morrison, S.J. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 2005, 121, 1109–1121. [Google Scholar] [CrossRef]
- Goessling, W.; North, T.E.; Loewer, S.; Lord, A.M.; Lee, S.; Stoick-Cooper, C.L.; Weidinger, G.; Puder, M.; Daley, G.Q.; Moon, R.T.; et al. Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration. Cell 2009, 136, 1136–1147. [Google Scholar] [CrossRef] [PubMed]
- Bhat, R.; Xue, Y.; Berg, S.; Hellberg, S.; Ormo, M.; Nilsson, Y.; Radesater, A.C.; Jerning, E.; Markgren, P.O.; Borgegard, T.; et al. Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. J. Biol. Chem. 2003, 278, 45937–45945. [Google Scholar] [CrossRef] [PubMed]
- Kyriakis, J.M.; Avruch, J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol. Rev. 2001, 81, 807–869. [Google Scholar] [CrossRef] [PubMed]
- Geest, C.R.; Coffer, P.J. MAPK signaling pathways in the regulation of hematopoiesis. J. Leukoc. Biol. 2009, 86, 237–250. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.; Kellner, J.; Liu, L.; Zhou, D. Inhibition of p38 mitogen-activated protein kinase promotes ex vivo hematopoietic stem cell expansion. Stem Cells Dev. 2011, 20, 1143–1152. [Google Scholar] [CrossRef]
- Kirito, K.; Fox, N.; Kaushansky, K. Thrombopoietin stimulates Hoxb4 expression: An explanation for the favorable effects of TPO on hematopoietic stem cells. Blood 2003, 102, 3172–3178. [Google Scholar] [CrossRef]
- Nagata, Y.; Moriguchi, T.; Nishida, E.; Todokoro, K. Activation of p38 MAP kinase pathway by erythropoietin and interleukin-3. Blood 1997, 90, 929–934. [Google Scholar] [CrossRef]
- Rausch, O.; Marshall, C.J. Cooperation of p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways during granulocyte colony-stimulating factor-induced hemopoietic cell proliferation. J. Biol. Chem. 1999, 274, 4096–4105. [Google Scholar] [CrossRef]
- Ito, K.; Hirao, A.; Arai, F.; Takubo, K.; Matsuoka, S.; Miyamoto, K.; Ohmura, M.; Naka, K.; Hosokawa, K.; Ikeda, Y.; et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat. Med. 2006, 12, 446–451. [Google Scholar] [CrossRef]
- Zhou, L.; Opalinska, J.; Verma, A. p38 MAP kinase regulates stem cell apoptosis in human hematopoietic failure. Cell Cycle 2007, 6, 534–537. [Google Scholar] [CrossRef]
- Pargellis, C.; Tong, L.; Churchill, L.; Cirillo, P.F.; Gilmore, T.; Graham, A.G.; Grob, P.M.; Hickey, E.R.; Moss, N.; Pav, S.; et al. Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat. Struct. Biol. 2002, 9, 268–272. [Google Scholar] [CrossRef] [PubMed]
- Campbell, R.M.; Anderson, B.D.; Brooks, N.A.; Brooks, H.B.; Chan, E.M.; De Dios, A.; Gilmour, R.; Graff, J.R.; Jambrina, E.; Mader, M.; et al. Characterization of LY2228820 dimesylate, a potent and selective inhibitor of p38 MAPK with antitumor activity. Mol. Cancer Ther. 2014, 13, 364–374. [Google Scholar] [CrossRef] [PubMed]
- Thalheimer, F.B.; Wingert, S.; De Giacomo, P.; Haetscher, N.; Rehage, M.; Brill, B.; Theis, F.J.; Hennighausen, L.; Schroeder, T.; Rieger, M.A. Cytokine-regulated GADD45G induces differentiation and lineage selection in hematopoietic stem cells. Stem Cell Rep. 2014, 3, 34–43. [Google Scholar] [CrossRef]
- Tesio, M.; Tang, Y.; Mudder, K.; Saini, M.; von Paleske, L.; Macintyre, E.; Pasparakis, M.; Waisman, A.; Trumpp, A. Hematopoietic stem cell quiescence and function are controlled by the CYLD-TRAF2-p38MAPK pathway. J. Exp. Med. 2015, 212, 525–538. [Google Scholar] [CrossRef] [PubMed]
- Hu, T.; Li, C.; Zhang, Y.; Wang, L.; Peng, L.; Cheng, H.; Wang, W.; Chu, Y.; Xu, M.; Cheng, T.; et al. Phosphoinositide-dependent kinase 1 regulates leukemia stem cell maintenance in MLL-AF9-induced murine acute myeloid leukemia. Biochem. Biophys. Res. Commun. 2015, 459, 692–698. [Google Scholar] [CrossRef] [PubMed]
- Mora, A.; Komander, D.; van Aalten, D.M.; Alessi, D.R. PDK1, the master regulator of AGC kinase signal transduction. Semin. Cell Dev. Biol. 2004, 15, 161–170. [Google Scholar] [CrossRef]
- Cantrell, D.A. Phosphoinositide 3-kinase signalling pathways. J. Cell Sci. 2001, 114 Pt 8, 1439–1445. [Google Scholar]
- Brader, S.; Eccles, S.A. Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. Tumori 2004, 90, 2–8. [Google Scholar] [CrossRef]
- Janus, J.M.; O’Shaughnessy, R.F.L.; Harwood, C.A.; Maffucci, T. Phosphoinositide 3-kinase-dependent signalling pathways in cutaneous squamous cell carcinomas. Cancers 2017, 9, 86. [Google Scholar] [CrossRef]
- Wang, W.; Sun, X.; Hu, T.; Wang, L.; Dong, S.; Gu, J.; Chu, Y.; Wang, X.; Li, Y.; Ru, Y.; et al. PDK1 regulates definitive HSCs via the FOXO pathway during murine fetal liver hematopoiesis. Stem Cell Res. 2018, 30, 192–200. [Google Scholar] [CrossRef]
- Alessi, D.R.; Sakamoto, K.; Bayascas, J.R. LKB1-dependent signaling pathways. Annu. Rev. Biochem. 2006, 75, 137–163. [Google Scholar] [CrossRef] [PubMed]
- Inoki, K.; Zhu, T.; Guan, K.L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003, 115, 577–590. [Google Scholar] [CrossRef]
- Corradetti, M.N.; Inoki, K.; Bardeesy, N.; DePinho, R.A.; Guan, K.L. Regulation of the TSC pathway by LKB1: Evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev. 2004, 18, 1533–1538. [Google Scholar] [CrossRef] [PubMed]
- Gwinn, D.M.; Shackelford, D.B.; Egan, D.F.; Mihaylova, M.M.; Mery, A.; Vasquez, D.S.; Turk, B.E.; Shaw, R.J. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 2008, 30, 214–226. [Google Scholar] [CrossRef] [PubMed]
- Nakada, D.; Saunders, T.L.; Morrison, S.J. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 2010, 468, 653–658. [Google Scholar] [CrossRef]
- Gan, B.; Hu, J.; Jiang, S.; Liu, Y.; Sahin, E.; Zhuang, L.; Fletcher-Sananikone, E.; Colla, S.; Wang, Y.A.; Chin, L.; et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature 2010, 468, 701–704. [Google Scholar] [CrossRef]
- Brault, L.; Gasser, C.; Bracher, F.; Huber, K.; Knapp, S.; Schwaller, J. PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers. Haematologica 2010, 95, 1004–1015. [Google Scholar] [CrossRef]
- Breuer, M.L.; Cuypers, H.T.; Berns, A. Evidence for the involvement of pim-2, a new common proviral insertion site, in progression of lymphomas. EMBO J. 1989, 8, 743–748. [Google Scholar] [CrossRef]
- Mikkers, H.; Allen, J.; Knipscheer, P.; Romeijn, L.; Hart, A.; Vink, E.; Berns, A. High-throughput retroviral tagging to identify components of specific signaling pathways in cancer. Nat. Genet. 2002, 32, 153–159. [Google Scholar] [CrossRef]
- Allen, J.D.; Verhoeven, E.; Domen, J.; van der Valk, M.; Berns, A. Pim-2 transgene induces lymphoid tumors, exhibiting potent synergy with c-myc. Oncogene 1997, 15, 1133–1141. [Google Scholar] [CrossRef]
- An, N.; Lin, Y.W.; Mahajan, S.; Kellner, J.N.; Wang, Y.; Li, Z.; Kraft, A.S.; Kang, Y. Pim1 serine/threonine kinase regulates the number and functions of murine hematopoietic stem cells. Stem Cells 2013, 31, 1202–1212. [Google Scholar] [CrossRef] [PubMed]
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Cho, H.J.; Lee, J.; Yoon, S.R.; Lee, H.G.; Jung, H. Regulation of Hematopoietic Stem Cell Fate and Malignancy. Int. J. Mol. Sci. 2020, 21, 4780. https://doi.org/10.3390/ijms21134780
Cho HJ, Lee J, Yoon SR, Lee HG, Jung H. Regulation of Hematopoietic Stem Cell Fate and Malignancy. International Journal of Molecular Sciences. 2020; 21(13):4780. https://doi.org/10.3390/ijms21134780
Chicago/Turabian StyleCho, Hee Jun, Jungwoon Lee, Suk Ran Yoon, Hee Gu Lee, and Haiyoung Jung. 2020. "Regulation of Hematopoietic Stem Cell Fate and Malignancy" International Journal of Molecular Sciences 21, no. 13: 4780. https://doi.org/10.3390/ijms21134780
APA StyleCho, H. J., Lee, J., Yoon, S. R., Lee, H. G., & Jung, H. (2020). Regulation of Hematopoietic Stem Cell Fate and Malignancy. International Journal of Molecular Sciences, 21(13), 4780. https://doi.org/10.3390/ijms21134780