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Mechanisms controlling hematopoietic stem cell functions during normal hematopoiesis and hematological malignancies

Advanced Review

Matthew R. Warr, Eric M. Pietras, Emmanuelle Passegué

Published Online: Mar 15 2011

DOI: 10.1002/wsbm.145

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Abstract Hematopoiesis, the process by which all mature blood cells are generated from multipotent hematopoietic stem cells (HSCs), is a finely tuned balancing act in which HSCs must constantly decide between different cell fates: to proliferate, to self‐renew or differentiate, to stay quiescent in the bone marrow niche or migrate to the periphery, to live or die. These fates are regulated by a complex interplay between cell‐extrinsic cues and cell‐intrinsic regulatory pathways whose function is to maintain a homeostatic balance between HSC self‐renewal and life‐long replenishment of lost blood cells. Improper regulation of these competing cellular programs can transform HSCs and progenitor cells into disease‐initiating leukemic stem cells (LSCs). Strikingly, many of the mechanisms required for maintenance of normal HSC fate decisions are equally critical for the aberrant functions of LSCs. Because of the inherent complexities of these molecular mechanisms, a systematic approach to understanding the regulatory networks underlying HSC self‐renewal is critical for uncovering the similarities and differences between HSCs and LSCs. In this review, we focus on recent developments in elucidating the regulatory networks governing normal HSC self‐renewal programs and their implications for leukemic transformation. We describe the current technical and methodological limitations in isolating and characterizing HSCs and LSCs, and the emerging approaches that may afford a better understanding of the regulation of normal and leukemic hematopoiesis. Finally, we discuss how such basic mechanistic information may be of use for the design of novel therapies that will selectively reprogram and/or eliminate LSCs. WIREs Syst Biol Med 2011 3 681–701 DOI: 10.1002/wsbm.145 This article is categorized under: Developmental Biology > Developmental Processes in Health and Disease Developmental Biology > Stem Cell Biology and Regeneration

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Hematopoietic cell differentiation is organized in a hierarchical fashion.

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Multiple signaling pathways from the niche are integrated in hematopoietic stem cell (HSC) to regulate self‐renewal.

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PI3‐kinase signaling pathway.

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Bmi1‐p53 cell intrinsic pathway.

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Leukemic stem cells (LSCs) may reside in distinct compartments and have both common and distinct features.

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References

Orkin, SH, Zon, LI. Hematopoiesis: an evolving paradigm for stem cell biology. Cell 2008, 132: 631–644.
Morrison, SJ, Spradling, AC. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 2008, 132:598–611.
Jude, CD, Gaudet, JJ, Speck, NA, Ernst, P. Leukemia and hematopoietic stem cells: balancing proliferation and quiescence. Cell Cycle 2008, 7:586–591.
Passegue, E. Hematopoietic stem cells, leukemic stem cells and chronic myelogenous leukemia. Cell Cycle 2005, 4:266–268.
Huntly, BJ, Gilliland, DG. Leukaemia stem cells and the evolution of cancer‐stem‐cell research. Nat Rev Cancer 2005, 5:311–321.
Elrick, LJ, Jorgensen, HG, Mountford, JC, Holyoake, TL. Punish the parent not the progeny. Blood 2005, 105:1862–1866.
Purton, LE, Scadden, DT. Limiting factors in murine hematopoietic stem cell assays. Cell Stem Cell 2007, 1:263–270.
Benveniste, P, Frelin, C, Janmohamed, S, Barbara, M, Herrington, R, Hyam, D, Iscove, NN. Intermediate‐term hematopoietic stem cells with extended but time‐limited reconstitution potential. Cell Stem Cell 2010, 6:48–58.
Schroeder, T. Hematopoietic stem cell heterogeneity: subtypes, not unpredictable behavior. Cell Stem Cell 2010, 6:203–207.
Kiel, MJ, Yilmaz, OH, Iwashita, T, Terhorst, C, Morrison, SJ. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 2005, 121:1109–1121.
Majeti, R, Park, CY, Weissman, IL. Identification of a hierarchy of multipotent hematopoietic progenitors in human cord blood. Cell Stem Cell 2007, 1:635–645.
Yilmaz, OH, Kiel, MJ, Morrison, SJ. SLAM family markers are conserved among hematopoietic stem cells from old and reconstituted mice and markedly increase their purity. Blood 2006, 107:924–930.
Bryder, D, Rossi, DJ, Weissman, IL. Hematopoietic stem cells: the paradigmatic tissue‐specific stem cell. Am J Pathol 2006, 169:338–346.
Santaguida, M, Schepers, K, King, B, Sabnis, AJ, Forsberg, EC, Attema, JL, Braun, BS, Passegue, E. JunB protects against myeloid malignancies by limiting hematopoietic stem cell proliferation and differentiation without affecting self‐renewal. Cancer Cell 2009, 15:341–352.
Spangrude, GJ, Heimfeld, S, Weissman, IL. Purification and characterization of mouse hematopoietic stem cells. Science 1988, 241:58–62.
Ikuta, K, Weissman, IL. Evidence that hematopoietic stem cells express mouse c‐kit but do not depend on steel factor for their generation. Proc Natl Acad Sci U S A 1192, 89:1502–1506.
Adolfsson, J, Borge, OJ, Bryder, D, Theilgaard‐Monch, K, Astrand‐Grundstrom, I, Sitnicka, E, Sasaki, Y, Jacobsen, SE. Upregulation of Flt3 expression within the bone marrow Lin(‐)Sca1(+)c‐kit(+) stem cell compartment is accompanied by loss of self‐renewal capacity. Immunity 2001, 15:659–669.
Christensen, JL, Weissman, IL. Flk‐2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long‐term stem cells. Proc Natl Acad Sci U S A 2001, 98:14541–14546.
Wagers, AJ, Sherwood, RI, Christensen, JL, Weissman, IL. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002, 297: 2256–2259.
Osawa, M, Hanada, K, Hamada, H, Nakauchi, H. Long‐term lymphohematopoietic reconstitution by a single CD34‐low/negative hematopoietic stem cell. Science 1996, 273:242–245.
Dykstra, B, Kent, D, Bowie, M, McCaffrey, L, Hamilton, M, Lyons, K, Lee, SJ, Brinkman, R, Eaves, C. Long‐term propagation of distinct hematopoietic differentiation programs in vivo. Cell Stem Cell 2007, 1:218–229.
Chen, CZ, Li, L, Li, M, Lodish, HF. The endoglin (positive) sca‐1(positive) rhodamine(low) phenotype defines a near‐homogeneous population of long‐term repopulating hematopoietic stem cells. Immunity 2003, 19:525–533.
Wilson, A, Laurenti, E, Oser, G, van der Wath, RC, Blanco‐Bose, W, Jaworski, M, Offner, S, Dunant, CF, Eshkind, L, Bockamp, E, et al. Hematopoietic stem cells reversibly switch from dormancy to self‐renewal during homeostasis and repair. Cell 2008, 135:1118–1129.
Weksberg, DC, Chambers, SM, Boles, NC, Goodell, MA. CD150‐ side population cells represent a functionally distinct population of long‐term hematopoietic stem cells. Blood 2008, 111:2444–2451.
Challen, GA, Boles, NC, Chambers, SM, Goodell, MA. Distinct hematopoietic stem cell subtypes are differentially regulated by TGF‐β1. Cell stem cell 2010, 6:265–278.
Wagers, AJ, Weissman, IL. Differential expression of alpha2 integrin separates long‐term and short‐term reconstituting Lin‐/loThy1.1(lo)c‐kit+ Sca‐1+ hematopoietic stem cells. Stem Cells 2006, 24: 1087–1094.
Balazs, AB, Fabian, AJ, Esmon, CT, Mulligan, RC. Endothelial protein C receptor (CD201) explicitly identifies hematopoietic stem cells in murine bone marrow. Blood 2006, 107:2317–2321.
Ooi, AG, Karsunky, H, Majeti, R, Butz, S, Vestweber, D, Ishida, T, Quertermous, T, Weissman, IL, Forsberg, EC. The adhesion molecule esam1 is a novel hematopoietic stem cell marker. Stem Cells 2009, 27:653–661.
Dick, JE, Guenechea, G, Gan, OI, Dorrell, C. In vivo dynamics of human stem cell repopulation in NOD/SCID mice. Ann N Y Acad Sci 2001, 938: 184–190.
Shultz, LD, Lyons, BL, Burzenski, LM, Gott, B, Chen, X, Chaleff, S, Kotb, M, Gillies, SD, King, M, Mangada, J, et al. Human lymphoid and myeloid cell development in NOD/LtSz‐scid IL2R gamma mice engrafted with mobilized human hemopoietic stem cells. J Immunol 2005, 174:6477–6489.
McCune, JM, Namikawa, R, Kaneshima, H, Shultz, LD, Lieberman, M, Weissman, IL. The SCID‐hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science 1988, 241:1632–1639.
Murray, L, Chen, B, Galy, A, Chen, S, Tushinski, R, Uchida, N, Negrin, R, Tricot, G, Jagannath, S, Vesole, D, et, al. Enrichment of human hematopoietic stem cell activity in the CD34+Thy‐1+Lin‐subpopulation from mobilized peripheral blood. Blood 1995, 85:368–378.
Bhatia, M, Wang, JC, Kapp, U, Bonnet, D, Dick, JE. Purification of primitive human hematopoietic cells capable of repopulating immune‐deficient mice. Proc Natl Acad Sci U S A 1197, 94:5320–5325.
Hogan, CJ, Shpall, EJ, Keller, G. Differential long‐term and multilineage engraftment potential from subfractions of human CD34+ cord blood cells transplanted into NOD/SCID mice. Proc Natl Acad Sci U S A 2002, 99:413–418.
McKenzie, JL, Takenaka, K, Gan, OI, Doedens, M, Dick, JE. Low rhodamine 123 retention identifies long‐term human hematopoietic stem cells within the Lin‐CD34+CD38‐population. Blood 2007, 109:543–545.
Valk‐Lingbeek, ME, Bruggeman, SW, van Lohuizen, M. Stem cells and cancer; the polycomb connection. Cell 2004, 118:409–418.
Sherr, CJ. The INK4a/ARF network in tumour suppression. Nat Rev Mol Cell Biol 2001, 2:731–737.
Zilfou, JT, Lowe, SW. Tumor suppressive functions of p53. Cold Spring Harb Perspect Biol 2009, 1:a001883.
Vousden, KH, Prives, C. Blinded by the light: the growing complexity of p53. Cell 2009, 137:413–431.
van der Lugt, NM, Domen, J, Linders, K, van Roon, M, Robanus‐Maandag, E, te Riele, H, van der Valk, M, Deschamps, J, Sofroniew, M, van Lohuizen M, et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi‐1 proto‐oncogene. Genes Dev 1994, 8:757–769.
Park, IK, Qian, D, Kiel, M, Becker, MW, Pihalja, M, Weissman, IL, Morrison, SJ, Clarke, MF. Bmi‐1 is required for maintenance of adult self‐renewing haematopoietic stem cells. Nature 2003, 423: 302–305.
Lessard, J, Sauvageau, G. Bmi‐1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 2003, 423:255–260.
Akashi, K, He, X, Chen, J, Iwasaki, H, Niu, C, Steenhard, B, Zhang, J, Haug, J, Li, L. Transcriptional accessibility for genes of multiple tissues and hematopoietic lineages is hierarchically controlled during early hematopoiesis. Blood 2003, 101:383–389.
Oguro, H, Iwama, A, Morita, Y, Kamijo, T, van Lohuizen, M, Nakauchi, H. Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1‐deficient mice. J Exp Med 2006, 203:2247–2253.
Janzen, V, Forkert, R, Fleming, HE, Saito, Y, Waring, MT, Dombkowski, DM, Cheng, T, DePinho, RA, Sharpless, NE, Scadden, DT. Stem‐cell ageing modified by the cyclin‐dependent kinase inhibitor p16INK4a. Nature 2006, 443:421–426.
Attema, JL, Pronk, CJH, Norddahl, GL, Nygren, JM, Bryder, D. Hematopoietic stem cell ageing is uncoupled from p16 INK4A‐mediated senescence. Oncogene 2009, 28:2238–2243.
Haupt, Y, Bath, ML, Harris, AW, Adams, JM. bmi‐1 transgene induces lymphomas and collaborates with myc in tumorigenesis. Oncogene 1993, 8:3161–3164.
Haupt, Y, Alexander, WS, Barri, G, Klinken, SP, Adams, JM. Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu‐myc transgenic mice. Cell 1991, 65: 753–763.
Gil, J, Bernard, D, Peters, G. Role of polycomb group proteins in stem cell self‐renewal and cancer. DNA Cell Biol 2005, 24:117–125.
Wang, PY, Young, F, Chen, CY, Stevens, BM, Neering, SJ, Rossi, RM, Bushnell, T, Kuzin, I, Heinrich, D, Bottaro, A, et al. The biologic properties of leukemias arising from BCR/ABL‐mediated transformation vary as a function of developmental origin and activity of the p19ARF gene. Blood 2008, 112:4184–4192.
Chen, J, Ellison, FM, Keyvanfar, K, Omokaro, SO, Desierto, MJ, Eckhaus, MA, Young, NS. Enrichment of hematopoietic stem cells with SLAM and LSK markers for the detection of hematopoietic stem cell function in normal and Trp53 mice. Exp Hematol 2008, 36:1236–1243.
TeKippe, M, Harrison, DE, Chen, J. Expansion of hematopoietic stem cell phenotype and activity in Trp53‐ mice. Exp Hematol 2003, 31:521–527.
Liu, Y, Elf, SE, Miyata, Y, Sashida, G, Liu, Y, Huang, G, Di Giandomenico, S, Lee, JM, Deblasio, A, Menendez, S, et al. p53 regulates hematopoietic stem cell quiescence. Cell stem cell 2009, 4:37–48.
Passegué, E, Wagers, A, Giuriato, S, Anderson, W. Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J Exp Med 2005, 202: 1599–1611.
Akala, OO, Park, IK, Qian, D, Pihalja, M, Becker, MW, Clarke, MF. Long‐term haematopoietic reconstitution by Trp53–/–p16Ink4a–/–p19Arf–/– multipotent progenitors. Nature 2008, 453:228–232.
Cheng, T, Rodrigues, N, Shen, H, Yang, Y, Dombkowski, D, Sykes, M, Scadden, DT. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 2000, 287:1804–1808.
Foudi, A, Hochedlinger, K, Van Buren, D, Schindler, JW, Jaenisch, R, Carey, V, Hock, H. Analysis of histone 2B‐GFP retention reveals slowly cycling hematopoietic stem cells. Nat Biotechnol 2009, 27:84–90.
van Os, R, Kamminga, LM, Ausema, A, Bystrykh, LV, Draijer, DP, van Pelt, K, Dontje, B, de Haan, G. A limited role for p21Cip1/Waf1 in maintaining normal hematopoietic stem cell functioning. Stem Cells 2007, 25:836–843.
Imamura, J, Miyoshi, I, Koeffler, HP. p53 in hematologic malignancies. Blood 1994, 84:2412–2421.
Viale, A, De Franco, F, Orleth, A, Cambiaghi, V, Giuliani, V, Bossi, D, Ronchini, C, Ronzoni, S, Muradore, I, Monestiroli, S, et al. Cell‐cycle restriction limits DNA damage and maintains self‐renewal of leukaemia stem cells. Nature 2009, 457:51–56.
Peterson, LF, Yan, M, Zhang, DE. The p21Waf1 pathway is involved in blocking leukemogenesis by the t(8;21) fusion protein AML1‐ETO. Blood 2007, 109:4392–4398.
Choudhury, AR, Ju, Z, Djojosubroto, MW, Schienke, A, Lechel, A, Schaetzlein, S, Jiang, H, Stepczynska, A, Wang, C, Buer, J, et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet 2007, 39:99–105.
Chalhoub, N, Baker, SJ. PTEN and the PI3‐kinase pathway in cancer. Annu Rev Pathol 2009, 4:127–150.
Zhang, J, Grindley, JC, Yin, T, Jayasinghe, S, He, XC, Ross, JT, Haug, JS, Rupp, D, Porter‐Westpfahl, KS, Wiedemann, LM, et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 2006, 441:518–522.
Yilmaz, OH, Valdez, R, Theisen, BK, Guo, W, Ferguson, DO, Wu, H, Morrison, SJ. Pten dependence distinguishes haematopoietic stem cells from leukaemia‐initiating cells. Nature 2006, 441:475–482.
Kharas, MG, Okabe, R, Ganis, JJ, Gozo, M, Khandan, T, Paktinat, M, Gilliland, DG, Gritsman, K. Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice. Blood 2010, 115: 1406–1415.
Chen, C, Liu, Y, Liu, R, Ikenoue, T, Guan, KL, 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.
Gan, B, Sahin, E, Jiang, S, Sanchez‐Aguilera, A, Scott, KL, Chin, L, Williams, DA, Kwiatkowski, DJ, DePinho, RA. mTORC1‐dependent and ‐independent regulation of stem cell renewal, differentiation, and mobilization. Proc Natl Acad Sci U S A 2008, 105:19384–19389.
Wullschleger, S, Loewith, R, Hall, MN. TOR signaling in growth and metabolism. Cell 2006, 124:471–484.
Yamazaki, S, Iwama, A, Takayanagi, S, Morita, Y, Eto, K, Ema, H, Nakauchi, H. Cytokine signals modulated via lipid rafts mimic niche signals and induce hibernation in hematopoietic stem cells. EMBO J 2006, 25:3515–3523.
Miyamoto, K, Araki, KY, 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.
Tothova, Z, Kollipara, R, Huntly, BJ, Lee, BH, Castrillon, DH, Cullen, DE, McDowell, EP, Lazo‐Kallanian, S, Williams, IR, Sears, C, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 2007, 128:325–339.
Juntilla, MM, Patil, VD, Calamito, M, Joshi, RP, Birnbaum, MJ, Koretzky, GA. AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species. Blood 2010, 115:4030–4038.
Ito, K, Bernardi, R, Pandolfi, PP. A novel signaling network as a critical rheostat for the biology and maintenance of the normal stem cell and the cancer‐initiating cell. Curr Opin Genet Dev 2009, 19:51–59.
Ito, K, Bernardi, R, Morotti, A, Matsuoka, S, Saglio, G, Ikeda, Y, Rosenblatt, J, Avigan, DE, Teruya‐Feldstein, J, Pandolfi, PP. PML targeting eradicates quiescent leukaemia‐initiating cells. Nature 2008, 453: 1072–1078.
Wilson, A, Oser, GM, Jaworski, M, Blanco‐Bose, WE, Laurenti, E, Adolphe, C, Essers, MA, Macdonald, HR, Trumpp, A. Dormant and self‐renewing hematopoietic stem cells and their niches. Ann N Y Acad Sci 2007, 1106:64–75.
Schofield, R. The relationship between the spleen colony‐forming cell and the haemopoietic stem cell. Blood Cells 1978, 4:7–25.
Kiel, MJ, Morrison, SJ. Uncertainty in the niches that maintain haematopoietic stem cells. Nat Rev Immunol 2008, 8:290–301.
Eliasson, P, Jönsson, J‐I. The hematopoietic stem cell niche: low in oxygen but a nice place to be. J Cell Physiol 2010, 222:17–22.
Calvi, LM, Adams, GB, Weibrecht, KW, Weber, JM, Olson, DP, Knight, MC, Martin, RP, Schipani, E, Divieti, P, Bringhurst, FR, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 2003, 425: 841–846.
Zhang, J, Niu, C, Ye, L, Huang, H, He, X, Tong, WG, Ross, J, Haug, J, Johnson, T, Feng, JQ, et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 2003, 425:836–841.
Chan, CKF, Chen, C‐C, Luppen, CA, Kim, J‐B, DeBoer, AT, Wei, K, Helms, JA, Kuo, CJ, Kraft, DL, Weissman, IL. Endochondral ossification is required for haematopoietic stem‐cell niche formation. Nature 2009, 457: 490–494.
Trumpp, A, Essers, M, Wilson, A. Awakening dormant haematopoietic stem cells. Nat Rev Immunol 2010, 10:201–209.
Isufi, I, Seetharam, M, Zhou, L, Sohal, D, Opalinska, J, Pahanish, P, Verma, A. Transforming growth factor‐β signaling in normal and malignant hematopoiesis. J Interferon Cytokine Res 2007, 27:543–552.
Singbrant, S, Karlsson, G, Ehinger, M, Olsson, K, Jaako, P, Miharada, K‐I, Stadtfeld, M, Graf, T, Karlsson, S. Canonical BMP signaling is dispensable for hematopoietic stem cell function in both adult and fetal liver hematopoiesis, but essential to preserve colon architecture. Blood 2010, 115:4689–4698.
Ruscetti, FW, Akel, S, Bartelmez, SH. Autocrine transforming growth factor‐β regulation of hematopoiesis: many outcomes that depend on the context. Oncogene 2005, 24:5751–5763.
Karlsson, G, Blank, U, Moody, JL, 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.
Piek, E, Heldin, CH, Ten Dijke, P. Specificity, diversity, and regulation in TGF‐β superfamily signaling. FASEB J 1999, 13:2105–2124.
Goey, H, Keller, JR, Back, T, Longo, DL, Ruscetti, FW, Wiltrout, RH. Inhibition of early murine hemopoietic progenitor cell proliferation after in vivo locoregional administration of transforming growth factor‐β 1. J Immunol 1989, 143:877–880.
Kulkarni, AB, Huh, CG, Becker, D, Geiser, A, Lyght, M, Flanders, KC, Roberts, AB, Sporn, MB, Ward, JM, Karlsson, S. Transforming growth factor β 1 mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A 1993, 90:770–774.
Dickson, MC, Martin, JS, Cousins, FM, Kulkarni, AB, Karlsson, S, Akhurst, RJ. Defective haematopoiesis and vasculogenesis in transforming growth factor‐β 1 knock out mice. Development 1995, 121:1845–1854.
Yaswen, L, Kulkarni, AB, Fredrickson, T, Mittleman, B, Schiffman, R, Payne, S, Longenecker, G, Mozes, E, Karlsson, S. Autoimmune manifestations in the transforming growth factor‐β 1 knockout mouse. Blood 1996, 87:1439–1445.
Oshima, M, Oshima, H, Taketo, MM. TGF‐β receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Dev Biol 1996, 179:297–302.
Larsson, J, Blank, U, Helgadottir, H, Bjornsson, JM, Ehinger, M, Goumans, MJ, Fan, X, Leveen, P, Karlsson, S. TGF‐β 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.
Levéen, P, Larsson, J, Ehinger, M, Cilio, CM, Sundler, M, Sjöstrand, LJ, Holmdahl, R, Karlsson, S. Induced disruption of the transforming growth factor β type II receptor gene in mice causes a lethal inflammatory disorder that is transplantable. Blood 2002, 100:560–568.
Larsson, J, Blank, U, Klintman, J, Magnusson, M, Karlsson, S. Quiescence of hematopoietic stem cells and maintenance of the stem cell pool is not dependent on TGF‐β signaling in vivo. Exp Hematol 2005, 33:592–596.
Larsson, J, Goumans, MJ, Sjostrand, LJ, van Rooijen, MA, Ward, D, Leveen, P, Xu, X, ten Dijke, P, Mummery, CL, Karlsson, S. Abnormal angiogenesis but intact hematopoietic potential in TGF‐β type I receptor‐deficient mice. EMBO J 2001, 20:1663–1673.
Leveen, P, Larsson, J, Ehinger, M, Cilio, CM, Sundler, M, Sjostrand, LJ, Holmdahl, R, Karlsson, S. Induced disruption of the transforming growth factor β type II receptor gene in mice causes a lethal inflammatory disorder that is transplantable. Blood 2002, 100:560–568.
Yamazaki, S, Iwama, A, Takayanagi, S‐I, Eto, K, Ema, H, Nakauchi, H. TGF‐β as a candidate bone marrow niche signal to induce hematopoietic stem cell hibernation. Blood 2009, 113:1250–1256.
Murohashi, I, Endho, K, Nishida, S, Yoshida, S, Jinnai, I, Bessho, M, Hirashima, K. Differential effects of TGF‐β 1 on normal and leukemic human hematopoietic cell proliferation. Exp Hematol 1995, 23:970–977.
Jonuleit, T, van der Kuip, H, Miething, C, Michels, H, Hallek, M, Duyster, J, Aulitzky, WE. Bcr‐Abl kinase down‐regulates cyclin‐dependent kinase inhibitor p27 in human and murine cell lines. Blood 2000, 96:1933–1939.
Hoshino, K, Quintas‐Cardama, A, Radich, J, Dai, H, Yang, H, Garcia‐Manero G. Downregulation of JUNB mRNA expression in advanced phase chronic myelogenous leukemia. Leuk Res 2009, 33:1361–1366.
Naka, K, Hoshii, T, Muraguchi, T, Tadokoro, Y, Ooshio, T, Kondo, Y, Nakao, S, Motoyama, N, Hirao, A. TGF‐β‐FOXO signalling maintains leukaemia‐initiating cells in chronic myeloid leukaemia. Nature 2010, 463:676–680.
Staal, FJT, Luis, TC. Wnt signaling in hematopoiesis: crucial factors for self‐renewal, proliferation, and cell fate decisions. J Cell Biochem 2010, 109:844–849.
Reya, T, Duncan, AW, Ailles, L, Domen, J, Scherer, DC, Willert, K, Hintz, L, Nusse, R, Weissman, IL. A role for Wnt signalling in self‐renewal of haematopoietic stem cells. Nature 2003, 423:409–414.
Baba, Y, Yokota, T, Spits, H, Garrett, KP, Hayashi, S‐I, Kincade, PW. Constitutively active β‐catenin promotes expansion of multipotent hematopoietic progenitors in culture. J Immunol 2006, 177:2294–2303.
Jeannet, G, Scheller, M, Scarpellino, L, Duboux, S, Gardiol, N, Back, J, Kuttler, F, Malanchi, I, Birchmeier, W, Leutz, A, et al. Long‐term, multilineage hematopoiesis occurs in the combined absence of β‐catenin and γ‐catenin. Blood 2008, 111:142–149.
Koch, U, Wilson, A, Cobas, M, Kemler, R, Macdonald, HR, Radtke, F. Simultaneous loss of β‐ and γ‐catenin does not perturb hematopoiesis or lymphopoiesis. Blood 2008, 111:160–164.
Zhao, C, Blum, J, Chen, A, Kwon, HY, Jung, SH, Cook, JM, Lagoo, A, Reya, T. Loss of β‐catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 2007, 12:528–541.
Fleming, HE, Janzen, V, Lo Celso, C, Guo, J, Leahy, KM, Kronenberg, HM, Scadden, DT. Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self‐renewal in vivo. Cell Stem Cell 2008, 2:274–283.
Luis, TC, Weerkamp, F, Naber, BAE, Baert, MRM, de Haas, EFE, Nikolic, T, Heuvelmans, S, De Krijger, RR, van Dongen, JJM, Staal, FJT. Wnt3a deficiency irreversibly impairs hematopoietic stem cell self‐renewal and leads to defects in progenitor cell differentiation. Blood 2009, 113:546–554.
Trowbridge, JJ, Scott, MP, Bhatia, M. Hedgehog modulates cell cycle regulators in stem cells to control hematopoietic regeneration. Proc Natl Acad Sci U S A 2006, 103:14134–14139.
Lane, SW, Sykes, SM, Al‐Shahrour, F, Shterental, S, Paktinat, M, Lo Celso, C, Jesneck, JL, Ebert, BL, Williams, DA, Gilliland, DG. The Apc(min) mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS. Blood 2010, 115:3489–3497.
Hu, Y, Chen, Y, Douglas, L, Li, S. β‐Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR‐ABL‐induced chronic myeloid leukemia. Leukemia 2009, 23:109–116.
Jamieson, CH, Ailles, LE, Dylla, SJ, Muijtjens, M, Jones, C, Zehnder, JL, Gotlib, J, Li, K, Manz, MG, Keating, A, et al. Granulocyte‐macrophage progenitors as candidate leukemic stem cells in blast‐crisis CML. N Engl J Med 2004, 351:657–667.
Abrahamsson, AE, Geron, I, Gotlib, J, Dao, K‐HT, Barroga, CF, Newton, IG, Giles, FJ, Durocher, J, Creusot, RS, Karimi, M, et al. Glycogen synthase kinase 3β missplicing contributes to leukemia stem cell generation. Proc Natl Acad Sci U S A 2009, 106:3925–3929.
Petropoulos, K, Arseni, N, Schessl, C, Stadler, CR, Rawat, VPS, Deshpande, AJ, Heilmeier, B, Hiddemann, W, Quintanilla‐Martinez, L, Bohlander, SK, et al. A novel role for Lef‐1, a central transcription mediator of Wnt signaling, in leukemogenesis. J Exp Med 2008, 205:515–522.
Wang, Y, Krivtsov, AV, Sinha, AU, North, TE, Goessling, W, Feng, Z, Zon, LI, Armstrong, SA. The Wnt/β‐catenin pathway is required for the development of leukemia stem cells in AML. Science 2010, 327:1650–1653.
Campbell, C, Risueno, RM, Salati, S, Guezguez, B, Bhatia, M. Signal control of hematopoietic stem cell fate: Wnt, Notch, and Hedgehog as the usual suspects. Curr Opin Hematol 2008, 15:319–325.
Kobune, M, Ito, Y, Kawano, Y, Sasaki, K, Uchida, H, Nakamura, K, Dehari, H, Chiba, H, Takimoto, R, Matsunaga, T, et al. Indian hedgehog gene transfer augments hematopoietic support of human stromal cells including NOD/SCID‐β2m–/– repopulating cells. Blood 2004, 104:1002–1009.
Bhardwaj, G, Murdoch, B, Wu, D, Baker, DP, Williams, KP, Chadwick, K, Ling, LE, Karanu, FN, Bhatia, M. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat Immunol 2001, 2:172–180.
Chung, UI, Schipani, E, McMahon, AP, Kronenberg, HM. Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development. J Clin Invest 2001, 107:295–304.
Dierks, C, Beigi, R, Guo, G‐R, Zirlik, K, Stegert, MR, Manley, P, Trussell, C, Schmitt‐Graeff, A, Landwerlin, K, Veelken, H, et al. Expansion of Bcr‐Abl‐positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 2008, 14:238–249.
Zhao, C, Beigi, R, Guo, G‐R, Zirlik, K, Stegert, MR, Manley, P, Trussell, C, Schmitt‐Graeff, A, Landwerlin, K, Veelken, H, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 2009, 458:776–779.
Merchant, A, Joseph, G, Wang, Q, Brennan, S, Matsui, W. Gli1 regulates the proliferation and differentiation of HSCs and myeloid progenitors. Blood 2010, 115:2391–2396.
Gao, J, Graves, S, Koch, U, Liu, S, Jankovic, V, Buonamici, S, El Andaloussi, A, Nimer, SD, Kee, BL, Taichman, R, et al. Hedgehog signaling is dispensable for adult hematopoietic stem cell function. Cell Stem Cell 2009, 4:548–558.
Hofmann, I, Stover, EH, Cullen, DE, Mao, J, Morgan, KJ, Lee, BH, Kharas, MG, Miller, PG, Cornejo, MG, Okabe, R, et al. Hedgehog signaling is dispensable for adult murine hematopoietic stem cell function and hematopoiesis. Cell Stem Cell 2009, 4:559–567.
Wu, M, Kwon, HY, Rattis, F, Blum, J, Zhao, C, Ashkenazi, R, Jackson, TL, Gaiano, N, Oliver, T, Reya, T. Imaging hematopoietic precursor division in real time. Cell Stem Cell 2007, 1:541–554.
Radtke, F, Fasnacht, N, Macdonald, HR. Notch signaling in the immune system. Immunity 2010, 32:14–27.
Weber, JM, Calvi, LM. Notch signaling and the bone marrow hematopoietic stem cell niche. Bone 2010, 46:281–285.
Schwanbeck, R, Schroeder, T, Henning, K, Kohlhof, H, Rieber, N, Erfurth, ML, Just, U. Notch signaling in embryonic and adult myelopoiesis. Cells Tissues Organs 2008, 188:91–102.
Bray, SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006, 7:678–689.
Kumano, K, Chiba, S, Kunisato, A, Sata, M, Saito, T, Nakagami‐Yamaguchi, E, Yamaguchi, T, Masuda, S, Shimizu, K, Takahashi, T, et al. Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells. Immunity 2003, 18:699–711.
Robert‐Moreno, A, Guiu, J, Ruiz‐Herguido, C, Lopez, ME, Ingles‐Esteve, J, Riera, L, Tipping, A, Enver, T, Dzierzak, E, Gridley, T, et al. Impaired embryonic haematopoiesis yet normal arterial development in the absence of the Notch ligand Jagged1. EMBO J 2008, 27:1886–1895.
Robert‐Moreno, A, Espinosa, L, de la Pompa, JL, Bigas, A. RBPjκ‐dependent Notch function regulates Gata2 and is essential for the formation of intra‐embryonic hematopoietic cells. Development 2005, 132:1117–1126.
Karanu, FN, Murdoch, B, Gallacher, L, Wu, DM, Koremoto, M, Sakano, S, Bhatia, M. The notch ligand jagged‐1 represents a novel growth factor of human hematopoietic stem cells. J Exp Med 2000, 192:1365–1372.
Butler, JM, Nolan, DJ, Vertes, EL, Varnum‐Finney, B, Kobayashi, H, Hooper, AT, Seandel, M, Shido, K, White, IA, Kobayashi, M, et al. Endothelial cells are essential for the self‐renewal and repopulation of Notch‐dependent hematopoietic stem cells. Cell Stem Cell 2010, 6:251–264.
Duncan, A, Rattis, F, DiMascio, L, Congdon, K. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance. Nat Immunol 2005, 6:314–322.
Karanu, FN, Murdoch, B, Miyabayashi, T, Ohno, M, Koremoto, M, Gallacher, L, Wu, D, Itoh, A, Sakano, S, Bhatia, M. Human homologues of δ − 1 and δ − 4 function as mitogenic regulators of primitive human hematopoietic cells. Blood 2001, 97: 1960–1967.
Varnum‐Finney, B, Xu, L, Brashem‐Stein, C, Nourigat, C, Flowers, D, Bakkour, S, Pear, WS, Bernstein, ID. Pluripotent, cytokine‐dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nat Med 2000, 6:1278–1281.
Varnum‐Finney, B, Purton, LE, Yu, M, Brashem‐Stein, C, Flowers, D, Staats, S, Moore, KA, Le Roux, I, Mann, R, Gray, G, et al. The Notch ligand, Jagged‐1, influences the development of primitive hematopoietic precursor cells. Blood 1998, 91:4084–4091.
Varnum‐Finney, B, Brashem‐Stein, C, Bernstein, ID. Combined effects of Notch signaling and cytokines induce a multiple log increase in precursors with lymphoid and myeloid reconstituting ability. Blood 2003, 101:1784–1789.
Stier, S, Cheng, T, Dombkowski, D, Carlesso, N, Scadden, DT. Notch1 activation increases hematopoietic stem cell self‐renewal in vivo and favors lymphoid over myeloid lineage outcome. Blood 2002, 99: 2369–2378.
Mancini, SJC, Mantei, N, Dumortier, A, Suter, U, Macdonald, HR, Radtke, F. Jagged1‐dependent Notch signaling is dispensable for hematopoietic stem cell self‐renewal and differentiation. Blood 2005, 105: 2340–2342.
Maillard, I, Koch, U, Dumortier, A, Shestova, O, Xu, L, Sai, H, Pross, SE, Aster, JC, Bhandoola, A, Radtke, F, et al. Canonical notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. Cell Stem Cell 2008, 2:356–366.
Yin, D‐D, Fan, F‐Y, Hu, X‐B, Hou, L‐H, Zhang, X‐P, Liu, L, Liang, Y‐M, Han, H. Notch signaling inhibits the growth of the human chronic myeloid leukemia cell line K562. Leuk Res 2009, 33:109–114.
Kim, Y‐W, Koo, B‐K, Jeong, H‐W, Yoon, M‐J, Song, R, Shin, J, Jeong, D‐C, Kim, S‐H, Kong Y‐Y. Defective Notch activation in microenvironment leads to myeloproliferative disease. Blood 2008, 112:4628–4638.
Chiaramonte, R, Basile, A, Tassi, E, Calzavara, E, Cecchinato, V, Rossi, V, Biondi, A, Comi, P. A wide role for NOTCH1 signaling in acute leukemia. Cancer Lett 2005, 219:113–120.
Gal, H, Amariglio, N, Trakhtenbrot, L, Jacob‐Hirsh, J, Margalit, O, Avigdor, A, Nagler, A, Tavor, S, Ein‐Dor, L, Lapidot, T, et al. Gene expression profiles of AML derived stem cells; similarity to hematopoietic stem cells. Leukemia 2006, 20:2147–2154.
Demarest, RM, Ratti, F, Capobianco, AJ. It`s T‐ALL about Notch. Oncogene 2008, 27:5082–5091.
Tsiftsoglou, AS, Bonovolias, ID, Tsiftsoglou, SA. Multilevel targeting of hematopoietic stem cell self‐renewal, differentiation and apoptosis for leukemia therapy. Pharmacol Ther 2009, 122:264–280.
Broske, AM, Vockentanz, L, Kharazi, S, Huska, MR, Mancini, E, Scheller, M, Kuhl, C, Enns, A, Prinz, M, Jaenisch, R, et al. DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nat Genet 2009, 41:1207–1215.
Eminli, S, Foudi, A, Stadtfeld, M, Maherali, N, Ahfeldt, T, Mostoslavsky, G, Hock, H, Hochedlinger, K. Differentiation stage determines potential of hematopoietic cells for reprogramming into induced pluripotent stem cells. Nat Genet 2009, 41:968–976.
Majeti, R, Becker, MW, Tian, Q, Lee, T‐LM, Yan, X, Liu, R, Chiang, J‐H, Hood, L, Clarke, MF, Weissman, IL. Dysregulated gene expression networks in human acute myelogenous leukemia stem cells. Proc Natl Acad Sci U S A 2009, 106:3396–3401.
Forsberg, EC, Passegué E, Prohaska, SS, Wagers, AJ, Koeva, M, Stuart, JM, Weissman, IL. Molecular signatures of quiescent, mobilized and leukemia‐initiating hematopoietic stem cells. PLoS One 2010, 5:e8785.
Saito, Y, Uchida, N, Tanaka, S, Suzuki, N, Tomizawa‐Murasawa, M, Sone, A, Najima, Y, Takagi, S, Aoki, Y, Wake, A, et al. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat Biotechnol 2010, 28:275–280.

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