Abstract
Tumors contain a fraction of cancer stem cells that maintain the propagation of the disease. The CD34+CD38− cells, isolated from acute myeloid leukemia (AML), were shown to be enriched leukemic stem cells (LSC). We isolated the CD34+CD38− cell fraction from AML and compared their gene expression profiles to the CD34+CD38+ cell fraction, using microarrays. We found 409 genes that were at least twofold over- or underexpressed between the two cell populations. These include underexpression of DNA repair, signal transduction and cell cycle genes, consistent with the relative quiescence of stem cells, and chromosomal aberrations and mutations of leukemic cells. Comparison of the LSC expression data to that of normal hematopoietic stem cells (HSC) revealed that 34% of the modulated genes are shared by both LSC and HSC, supporting the suggestion that the LSC originated within the HSC progenitors. We focused on the Notch pathway since Jagged-2, a Notch ligand was found to be overexpressed in the LSC samples. We show that DAPT, an inhibitor of gamma-secretase, a protease that is involved in Jagged and Notch signaling, inhibits LSC growth in colony formation assays. Identification of additional genes that regulate LSC self-renewal may provide new targets for therapy.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Passegue E, Jamieson CH, Ailles LE, Weissman IL . Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci USA 2003; 100 (Suppl 1): 11842–11849.
Hope KJ, Jin L, Dick JE . Human acute myeloid leukemia stem cells. Arch Med Res 2003; 34: 507–514.
Pardal R, Clarke MF, Morrison SJ . Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 2003; 3: 895–902.
Reya T, Morrison SJ, Clarke MF, Weissman IL . Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105–111.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF . Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100: 3983–3988.
Singh SK, Clarke ID, Hide T, Dirks PB . Cancer stem cells in nervous system tumors. Oncogene 2004; 23: 7267–7273.
Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367: 645–648.
Bonnet D, Dick JE . Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730–737.
Rombouts WJ, Martens AC, Ploemacher RE . Identification of variables determining the engraftment potential of human acute myeloid leukemia in the immunodeficient NOD/SCID human chimera model. Leukemia 2000; 14: 889–897.
van Rhenen A, Feller N, Kelder A, Westra AH, Rombouts E, Zweegman S et al. High stem cell frequency in acute myeloid leukemia at diagnosis predicts high minimal residual disease and poor survival. Clin Cancer Res 2005; 11: 6520–6527.
Till JE, McCulloch EA . A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 1961; 14: 213–222.
Cozzio A, Passegue E, Ayton PM, Karsunky H, Cleary ML, Weissman IL . Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev 2003; 17: 3029–3035.
Taipale J, Beachy PA . The Hedgehog and Wnt signalling pathways in cancer. Nature 2001; 411: 349–354.
Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 2003; 423: 302–305.
Costello RT, Mallet F, Gaugler B, Sainty D, Arnoulet C, Gastaut JA et al. Human acute myeloid leukemia CD34+/CD38− progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities. Cancer Res 2000; 60: 4403–4411.
Benjamini Y, Hochberg Y . Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc 1995; 57: 289–300.
Dennis Jr G, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC et al. DAVID: database for annotation, visualization, and integrated discovery. Genome Biol 2003; 4: P3.
Rebhan M, Chalifa-Caspi V, Prilusky J, Lancet D . GeneCards: a novel functional genomics compendium with automated data mining and query reformulation support. Bioinformatics 1998; 14: 656–664.
Tsafrir D, Tsafrir I, Ein-Dor L, Zuk O, Notterman DA, Domany E . Sorting points into neighborhoods (SPIN): data analysis and visualization by ordering distance matrices. Bioinformatics 2005; 21: 2301–2308.
Georgantas RW, Tanadve V, Malehorn M, Heimfeld S, Chen C, Carr L et al. Microarray and serial analysis of gene expression analyses identify known and novel transcripts overexpressed in hematopoietic stem cells. Cancer Res 2004; 64: 4434–4441.
Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA, Lemischka IR . A stem cell molecular signature. Science 2002; 298: 601–604.
Toren A, Bielorai B, Jacob-Hirsch J, Fisher T, Kreiser D, Moran O et al. CD133-positive hematopoietic stem cell ‘stemness’ genes contain many genes mutated or abnormally expressed in leukemia. Stem Cells 2005; 23: 1142–1153.
Tavazoie S, Hughes JD, Campbell MJ, Cho RJ, Church GM . Systematic determination of genetic network architecture. Nat Genet 1999; 22: 281–285.
Guasch G, Fuchs E . Mice in the world of stem cell biology. Nat Genet 2005; 37: 1201–1206.
Karanu FN, Murdoch B, Gallacher L, Wu DM, Koremoto M, Sakano S et al. The notch ligand jagged-1 represents a novel growth factor of human hematopoietic stem cells. J Exp Med 2000; 192: 1365–1372.
Varnum-Finney B, Xu L, Brashem-Stein C, Nourigat C, Flowers D, Bakkour S et al. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nat Med 2000; 6: 1278–1281.
Duncan AW, Rattis FM, DiMascio LN, Congdon KL, Pazianos G, Zhao C et al. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance. Nat Immunol 2005; 6: 314–322.
O'Neil J, Calvo J, McKenna K, Krishnamoorthy V, Aster JC, Bassing CH et al. Activating Notch1 mutations in mouse models of T-ALL. Blood 2006; 107: 781–785.
Tohda S, Kogoshi H, Murakami N, Sakano S, Nara N . Diverse effects of the Notch ligands Jagged1 and Delta1 on the growth and differentiation of primary acute myeloblastic leukemia cells. Exp Hematol 2005; 33: 558–563.
van Es JH, Clevers H . Notch and Wnt inhibitors as potential new drugs for intestinal neoplastic disease. Trends Mol Med 2005; 11: 496–502.
Dovey HF, John V, Anderson JP, Chen LZ, de Saint Andrieu P, Fang LY et al. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem 2001; 76: 173–181.
Jordan CT, Upchurch D, Szilvassy SJ, Guzman ML, Howard DS, Pettigrew AL et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia 2000; 14: 1777–1784.
Huntly BJ, Gilliland DG . Blasts from the past: new lessons in stem cell biology from chronic myelogenous leukemia. Cancer Cell 2004; 6: 199–201.
Terpstra W, Ploemacher RE, Prins A, van Lom K, Pouwels K, Wognum AW et al. Fluorouracil selectively spares acute myeloid leukemia cells with long-term growth abilities in immunodeficient mice and in culture. Blood 1996; 88: 1944–1950.
Sjolund J, Manetopoulos C, Stockhausen MT, Axelson H . The Notch pathway in cancer: differentiation gone awry. Eur J Cancer 2005; 41: 2620–2629.
Ascano JM, Beverly LJ, Capobianco AJ . The C-terminal PDZ-ligand of JAGGED1 is essential for cellular transformation. J Biol Chem 2003; 278: 8771–8779.
Weng AP, Nam Y, Wolfe MS, Pear WS, Griffin JD, Blacklow SC et al. Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol 2003; 23: 655–664.
Weng AP, Ferrando AA, Lee W, Morris JPT, Silverman LB, Sanchez-Irizarry C et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004; 306: 269–271.
Huff CA, Matsui W, Smith BD, Jones RJ . The paradox of response and survival in cancer therapeutics. Blood 2006; 107: 431–434.
Angstreich GR, Matsui W, Huff CA, Vala MS, Barber J, Hawkins AL et al. Effects of imatinib and interferon on primitive chronic myeloid leukaemia progenitors. Br J Haematol 2005; 130: 373–381.
Acknowledgements
We thank the Kahn Family Foundation for their generous support. This research was partially supported by the Wolfson Family Charitable Trust on Tumor Cell Diversity, by the Israel Academy of Science, and by grants from Ruth & Allen Zeigler for Stem Cell Research.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)
Supplementary information
Rights and permissions
About this article
Cite this article
Gal, H., Amariglio, N., Trakhtenbrot, L. et al. Gene expression profiles of AML derived stem cells; similarity to hematopoietic stem cells. Leukemia 20, 2147–2154 (2006). https://doi.org/10.1038/sj.leu.2404401
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2404401
Keywords
This article is cited by
-
BMP signaling in cancer stemness and differentiation
Cell Regeneration (2023)
-
Uncovering expression signatures of synergistic drug responses via ensembles of explainable machine-learning models
Nature Biomedical Engineering (2023)
-
PD-1 signalling defines and protects leukaemic stem cells from T cell receptor-induced cell death in T cell acute lymphoblastic leukaemia
Nature Cell Biology (2023)
-
Deciphering molecular heterogeneity in pediatric AML using a cancer vs. normal transcriptomic approach
Pediatric Research (2021)
-
Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain
Nature Chemical Biology (2021)