Abstract
Acute myeloid leukemias (AML) are considered to be clonal disorders involving early hematopoietic progenitor cells. The recent advances in characterization of early stem cells give rise to the question whether it is possible to distinguish healthy progenitors from cells of the leukemic clone in leukemia patients. Differences and similarities in phenotype, genotype and biology are described for leukemic cells and normal hematological progenitors. Recent new insights into human stem cell development offer the perspective that distinction between benign and malignant progenitors might be possible in the future at a very early stage of maturation.
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
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C . Proposals for the classification of the acute leukaemias. French–American–British (FAB) co-operative group Br J Haematol 1976 33: 451–458
Civin CI, Strauss LC, Brovall C, Fackler MJ, Schwartz JF, Shaper JH . Antigenic analysis of hematopoiesis. III. A hematopoietic progenitor cell surface antigen defined by a monoclonal antibody raised against KG- 1a cells J Immunol 1984 133: 157–165
Zanjani ED, Almeida-Porada G, Livingston AG, Flake AW, Ogawa M . Human bone marrow CD34− cells engraft in vivo and undergo multilineage expression that includes giving rise to CD34+ cells (see comments) Exp Hematol 1998 26: 353–360
Zanjani ED, Almeida-Porada G, Livingston AG, Porada CD, Ogawa M . Engraftment and multilineage expression of human bone marrow CD34− cells in vivo Ann NY Acad Sci 1999 872: 220–231; discussion 231 – 232
Larochelle A, Vormoor J, Hanenberg H, Wang JC, Bhatia M, Lapidot T, Moritz T, Murdoch B, Xiao XL, Kato I, Williams DA, Dick JE . Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: implications for gene therapy Nature Med 1996 2: 1329–1337
Murray L, Chen B, Galy A, Chen S, Tushinski R, Uchida N, Negrin R, Tricot G, Jagannath S, Vesole D, Barlogie B, Hoffman R, Tsukamoto A . Enrichment of human hematopoietic stem cell activity in the CD34+Thy− 1+Lin− subpopulation from mobilized peripheral blood Blood 1995 85: 368–378
Humeau L, Bardin F, Maroc C, Alario T, Galindo R, Mannoni P, Chabannon C . Phenotypic, molecular, and functional characterization of human peripheral blood CD34+/THY1+ cells Blood 1996 87: 949–955
de Wynter EA, Buck D, Hart C, Heywood R, Coutinho LH, Clayton A, Rafferty JA, Burt D, Guenechea G, Bueren JA, Gagen D, Fairbairn LJ, Lord BI, Testa NG . CD34+AC133+ cells isolated from cord blood are highly enriched in long-term culture-initiating cells, NOD/SCID-repopulating cells and dendritic cell progenitors Stem Cells 1998 16: 387–396
Burchert A, Notter M, Menssen HD, Schwartz S, Knauf W, Neubauer A, Thiel E . CD82 (KAI1), a member of the tetraspan family, is expressed on early haemopoietic progenitor cells and up-regulated in distinct human leukaemias Br J Haematol 1999 107: 494–504
Ziegler BL, Valtieri M, Porada GA, De Maria R, Muller R, Masella B, Gabbianelli M, Casella I, Pelosi E, Bock T, Zanjani ED, Peschle C . KDR receptor: a key marker defining hematopoietic stem cells Science 1999 285: 1553–1558
Gehling UM, Ergun S, Schumacher U, Wagener C, Pantel K, Otte M, Schuch G, Schafhausen P, Mende T, Kilic N, Kluge K, Schafer B, Hossfeld DK, Fiedler W . In vitro differentiation of endothelial cells from AC133-positive progenitor cells (in process citation) Blood 2000 95: 3106–3112
Seiffert M, Cant C, Chen Z, Rappold I, Brugger W, Kanz L, Brown EJ, Ullrich A, HJ Bh . Human signal-regulatory protein is expressed on normal, but not on subsets of leukemic myeloid cells and mediates cellular adhesion involving Its counterreceptor CD47 Blood 1999 94: 3633–3643
Ashman LK, Cambareri AC, Levinsky RJ, Juttner CA . Expression of the YB5.B8 antigen (c-kit protooncogene product) in normal human bone marrow Blood 1991 78: 30–37
Sogo S, Inaba M, Ogata H, Hisha H, Adachi Y, Mori S, Toki J, Yamanishi K, Kanzaki H, Adachi M, Ikehara S . Induction of c-kit molecules on human CD34+/c-kit < low cells: evidence for CD34+/c-kit < low cells as primitive hematopoietic stem cells Stem Cells 1997 15: 420–429
Blair A, Hogge DE, Sutherland HJ . Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD34(+)/CD71(−)/HLA-DR Blood 1998 92: 4325–4335
Roy V, Miller JS, Verfaillie CM . Phenotypic and functional characterization of committed and primitive myeloid and lymphoid hematopoietic precursors in human fetal liver Exp Hematol 1997 25: 387–394
Kollet O, Aviram R, Chebath J, Ben-Hur H, Nagler A, Shultz L, Revel M, Lapidot T . The soluble interleukin-6 (IL-6) receptor/IL-6 fusion protein enhances in vitro maintenance and proliferation of human CD34(+)CD38(−/low) cells capable of repopulating severe combined immunodeficiency mice Blood 1999 94: 923–931
Gross S, Helm K, Gruntmeir JJ, Stillman WS, Pyatt DW, Irons RD . Characterization and phenotypic analysis of differentiating CD34+ human bone marrow cells in liquid culture Eur J Haematol 1997 59: 318–326
Bhatia M, Bonnet D, Murdoch B, Gan OI, Dick JE . A newly discovered class of human hematopoietic cells with SCID-repopulating activity (see comments) Nature Med 1998 4: 1038–1045
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
Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC . Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo J Exp Med 1996 183: 1797–1806
Goodell MA, Rosenzweig M, Kim H, Marks DF, DeMaria M, Paradis G, Grupp SA, Sieff CA, Mulligan RC, Johnson RP . Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species Nature Med 1997 3: 1337–1345
Sato T, Laver JH, Ogawa M . Reversible expression of CD34 by murine hematopoietic stem cells (see comments) Blood 1999 94: 2548–2554
Nakamura Y, Ando K, Chargui J, Kawada H, Sato T, Tsuji T, Hotta T, Kato S . Ex vivo generation of CD34(+) cells from CD34(−) hematopoietic cells Blood 1999 94: 4053–4059
Goodell MA . Introduction: focus on hematology. CD34(+) or CD34(−): does it really matter? (comment) Blood 1999 94: 2545–2547
Bjornson CR, Rietze RL, Reynolds BA, Magli MC, Vescovi AL . Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo (see comments) Science 1999 283: 534–537
Jackson KA, Mi T, Goodell MA . Hematopoietic potential of stem cells isolated from murine skeletal muscle (in process citation) Proc Natl Acad Sci USA 1999 96: 14482–14486
Loeb LA . Cancer cells exhibit a mutator phenotype Adv Cancer Res 1998 72: 25–56
Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, Rees J, Hann I, Stevens R, Burnett A, Goldstone A . The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial Blood 1998 92: 2322–2333
Yunis JJ, Brunning RD, Howe RB, Lobell M . High-resolution chromosomes as an independent prognostic indicator in adult acute nonlymphocytic leukemia New Engl J Med 1984 311: 812–818
Frank R, Zhang J, Uchida H, Meyers S, Hiebert SW, Nimer SD . The AML1/ETO fusion protein blocks transactivation of the GM-CSF promoter by AML 1B Oncogene 1995 11: 2667–2674
Meyers S, Lenny N, Hiebert SW . The t(8;21) fusion protein interferes with AML-1B-dependent transcriptional activation Mol Cell Biol 1995 15: 1974–1984
Rhoades KL, Hetherington CJ, Rowley JD, Hiebert SW, Nucifora G, Tenen DG, Zhang DE . Synergistic up-regulation of the myeloid-specific promoter for the macrophage colony-stimulating factor receptor by AML1 and the t(8;21) fusion protein may contribute to leukemogenesis Proc Natl Acad Sci USA 1996 93: 11895–11900
Ahn MY, Huang G, Bae SC, Wee HJ, Kim WY, Ito Y . Negative regulation of granulocytic differentiation in the myeloid precursor cell line 32Dc13 by ear-2, a mammalian homolog of Drosophila seven-up, and a chimeric leukemogenic gene, AML1/ETO Proc Natl Acad Sci USA 1998 95: 1812–1817
Friedman AD . Leukemogenesis by CBF oncoproteins Leukemia 1999 13: 1932–1942
Zent C, Rowley JD, Nucifora G . Rearrangements of the AML1/CBFA2 gene in myeloid leukemia with the 3;21 translocation: in vitro and in vivo studies Leukemia 1997 11: (Suppl. 3) 273–278
Rubnitz JE, Pui CH, Downing JR . The role of TEL fusion genes in pediatric leukemias Leukemia 1999 13: 6–13
Look AT . Oncogenic transcription factors in the human acute leukemias Science 1997 278: 1059–1064
Lim LC, Heng KK, Vellupillai M, Tan LT, Boey BC, Lau LC, How GF . Molecular and phenotypic spectrum of de novo Philadelphia positive acute leukemia Int J Mol Med 1999 4: 665–667
Appelbaum FR, Gilliland DG, Tallmann MS . The biology and treatment of acute myeloid leukemia American Society of Hematology Education Program Book 1998 pp 15–43
Pedersen-Bjergaard J, Janssen JWG, Lyons J, Philip P, Bartram CR . Point mutations of the ras protooncogenes and chromosome aberrations on acute nonlymphoblastic leukemia and preleukemia related to therapy with alkylating agents Cancer Res 1988 48: 1812–1817
Neubauer A, Dodge R, George SL, Davey FR, Silver RT, Schiffer CA, Mayer R, Ball ED, Wurster-Hill D, Bloomfield CD, Liu ET . Prognostic importance of mutations in the ras protooncogenes in de novo acute myeloid leukemia Blood 1994 83: 1603–1611
Schmidt CA, Przybylski G, Vogel D, Ludwig WD, Oettle H, Neubauer A, Siegert W . ras point mutations occur in acute myeloid leukemia with illegitimate T-cell receptor delta gene rearrangement Leukemia 1994 8: 102–105
Seliger B, Papadileris S, Vogel D, Hess G, Brendel C, Storkel S, Oertel J, Kolbe K, Huber C, Huhn D, Neubauer A . Analysis of p53 and mdm-2 gene in acute myeloid leukemia Eur J Haematol 1996 57: 230–240
Slingerland JM, Minden MD, Benchimol S . Mutation of the p53 gene in human acute myelogeneous leukemia Blood 1991 77: 1500–1507
Marie JP, Legrand O . MDR1/P-GP expression as a prognostic factor in acute leukemias Adv Exp Med Biol 1999 457: 1–9
Rombouts WJ, Broyl A, Martens AC, Slater R, Ploemacher RE . Human acute myeloid leukemia cells with internal tandem duplications in the Flt3 gene show reduced proliferative ability in stroma supported long-term cultures Leukemia 1999 13: 1071–1078
Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, Asou N, Kuriyama K, Jinnai I, Shimazaki C, Akiyama H, Saito K, Oh H, Motoji T, Omoto E, Saito H, Ohno R, Ueda R . Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia Blood 1999 93: 3074–3080
Xu F, Taki T, Yang HW, Hanada R, Hongo T, Ohnishi H, Kobayashi M, Bessho F, Yanagisawa M, Hayashi Y . Tandem duplication of the FLT3 gene is found in acute lymphoblastic leukaemia as well as acute myeloid leukaemia but not in myelodysplastic syndrome or juvenile chronic myelogenous leukaemia in children Br J Haematol 1999 105: 155–162
Alitalo K, Saksela K, Winqvist R, Alitalo R, Keski-Oja J, Laiho M, Ilvonen M, Knuutila S, Delachapelle A . Acute myelogenous leukemia with c-myc amplification and double minute chromosome Lancet 1985 11: 1035–1038
Baer MR, Augustinos P, Kinniburgh AJ . Defective c-myc and c-myb RNA turnover in acute myeloid leukemia cells Blood 1992 79: 1319–1326
Thorsteinsdottir U, Sauvageau G, Hough MR, Dragowska W, Lansdorp PM, Lawrence HJ, Largman C, Humphries RK . Overexpression of HOXA10 in murine hematopoietic cells perturbs both myeloid and lymphoid differentiation and leads to acute myeloid leukemia Mol Cell Biol 1997 17: 495–505
Okabe-Kado J, Kasukabe T, Honma Y . Differentiation inhibitory factor Nm23 as a prognostic factor for acute myeloid leukemia Leuk Lymphoma 1998 32: 19–28
Okuda T, Cai Z, Yang S, Lenny N, Lyu CJ, van Deursen JM, Harada H, Downing JR . Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors Blood 1998 91: 3134–3143
Castilla L, Bodine D, Garrett L, Liu P . Leukemia development by the induction of a second ‘hit’ in chimeric mice containing CBF-beta-MYH11 ES cells Blood 1998 92: 214a
Bloomfield CD, Lawrence D, Byrd JC, Carroll A, Pettenati MJ, Tantravahi R, Patil SR, Davey FR, Berg DT, Schiffer CA, Arthur DC, Mayer RJ . Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype Cancer Res 1998 58: 4173–4179
DeVita VTJ, Hellman S, Rosenberg SA . Cancer – Principles and Practice of Oncology, 4th edn JB Lippincott Co: Philidelphia 1993
Buhring HJ, Seiffert M, Marxer A, Weiss B, Faul C, Kanz L, Brugger W . AC133 antigen expression is not restricted to acute myeloid leukemia blasts but is also found on acute lymphoid leukemia blasts and on a subset of CD34+ B-cell precursors (letter) Blood 1999 94: 832–833
Horn PA, Tesch H, Staib P, Kube D, Diehl V, Voliotis D . Expression of AC133, a novel hematopoietic precursor antigen, on acute myeloid leukemia cells (letter) Blood 1999 93: 1435–1437
Drexler HG, Meyer C, Quentmeier H . Effects of FLT3 ligand on proliferation and survival of myeloid leukemia cells Leuk Lymphoma 1999 33: 83–91
De Waele M, Renmans W, Jochmans K, Schots R, Lacor P, Trullemans F, Otten J, Balduck N, Vander Gucht K, Van Camp B, Van Riet I . Different expression of adhesion molecules on CD34+ cells in AML and B- lineage ALL and their normal bone marrow counterparts Eur J Haematol 1999 63: 192–201
Costello R, Mallet F, Chambost H, Sainty D, Arnoulet C, Gastaut JA, Olive D . The immunophenotype of minimally differentiated acute myeloid leukemia (AML-MO): reduced immunogenicity and high frequency of CD34+/CD38− leukemic progenitors Leukemia 1999 13: 1513–1518
Schwartz S, Heinecke A, Zimmermann M, Creutzig U, Schoch C, Harbott J, Fonatsch C, Loffler H, Buchner T, Ludwig WD, Thiel E . Expression of the C-kit receptor (CD117) is a feature of almost all subtypes of de novo acute myeloblastic leukemia (AML), including cytogenetically good-risk AML, and lacks prognostic significance Leuk Lymphoma 1999 34: 85–94
Wittebol S, Raymakers R, van de Locht L, Mensink E, de Witte T . In AML t(8;21) colony growth of both leukemic and residual normal progenitors is restricted to the CD34+, lineage-negative fraction Leukemia 1998 12: 1782–1788
Miyamoto T, Nagafuji K, Akashi K, Harada M, Kyo T, Akashi T, Takenaka K, Mizuno S, Gondo H, Okamura T, Dohy H, Niho Y . Persistence of multipotent progenitors expressing AML1/ETO transcripts in long-term remission patients with t(8;21) acute myelogenous leukemia Blood 1996 87: 4789–4796
Edwards RH, Wasik MA, Finan J, Rodriguez R, Moore J, Kamoun M, Rennert H, Bird J, Nowell PC, Salhany KE . Evidence for early hematopoietic progenitor cell involvement in acute promyelocytic leukemia Am J Clin Pathol 1999 112: 819–827
Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE . A cell initiating human acute myeloid leukemia after transplantation into SCID mice Nature 1994 367: 645–648
Blair A, Hogge DE, Ailles LE, Lansdorp PM, Sutherland HJ . Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo Blood 1997 89: 3104–3112
Bonnet D, Dick JE . Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell Nature Med 1997 3: 730–737
Brendel C, Mohr B, Schimmelpfennig C, Muller J, Bornhauser M, Schmidt M, Ritter M, Ehninger G, Neubauer A . Detection of cytogenetic aberrations both in CD90 (Thy-1)-positive and (Thy-1)-negative stem cell (CD34) subfractions of patients with acute and chronic myeloid leukemias Leukemia 1999 13: 1770–1775
Verfaille CM, Miller WJ, Boylan K, McGlave PB . Selection of benign primitive hematopoietic progenitors in chronic myelogeneous leukemia on the basis of HLA-DR antigen expression Blood 1992 79: 1003–1010
Jiang X, Lopez A, Holyoake T, Eaves A, Eaves C . Autocrine production and action of IL-3 and granulocyte colony-stimulating factor in chronic myeloid leukemia Proc Natl Acad Sci USA 1999 96: 12804–12809
Sokolic RA, Ferguson W, Mark HF . Discordant detection ofmonosomy 7 by GTG-banding and FISH in a patient with Schwachman–Diamond syndrome without evidence of myelodysplasticsyndrome or acute myelogenous leukemia Cancer Genet Cytogenet 1999 115: 106–113
Tanaka K, Arif M, Eguchi M, Shintani T, Kumaravel TS, Asaoku H, Kyo T, Dohy H, Kamada N . Interphase fluorescence in situ hybridization overcomes pitfalls of G-banding analysis with special reference to underestimation of chromosomal aberration rates Cancer Genet Cytogenet 1999 115: 32–38
Feuring-Buske M, Haase D, Buske C, Hiddemann W, Wormann B . Clonal chromosomal abnormalities in the stem cell compartment of patients with acute myeloid leukemia in morphological complete remission Leukemia 1999 13: 386–392
Ritter M, de Kant E, Huhn D, Neubauer A . Detection of DNA methylation in human leukemias by differential polymerase chain reaction Leukemia 1995 9: 915–921
Bloomfield C, Shuma C, Regal L, Philip P, Hossfeld D, Hagemeijer A, Garson O, Peterson B, Sakurai M, Alimena G, Berger R, Rowley J, Ruutu T, Mitelman F, Dewald G, Swansbury J . Long-term survival of patients with acute myeloid leukemia Cancer 1997 80: 2191–2198
Byrd JC, Dodge RK, Carroll A, Baer MR, Edwards C, Stamberg J, Qumsiyeh M, Moore JO, Mayer RJ, Davey F, Schiffer CA, Bloomfield CD . Patients with t(8;21)(q22;q22) and acute myeloid leukemia have superior failure-free and overall survival when repetitive cycles of high-dose cytarabine are administered (in process citation) J Clin Oncol 1999 17: 3767–3775
Kwong YL, Ng MH, Ma SK . Familial acute myeloid leukemia with monosomy 7: late onset and involvement of a multipotential progenitor cell (in process citation) Cancer Genet Cytogenet 2000 116: 170–173
Cignetti A, Bryant E, Allione B, Vitale A, Foa R, Cheever MA . CD34(+) acute myeloid and lymphoid leukemic blasts can be induced to differentiate into dendritic cells Blood 1999 94: 2048–2055
Charrad RS, Li Y, Delpech B, Balitrand N, Clay D, Jasmin C, Chomienne C, Smadja-Joffe F . Ligation of the CD44 adhesion molecule reverses blockage of differentiation in human acute myeloid leukemia (see comments) Nature Med 1999 5: 669–676
Saitoh K, Miura I, Takahashi N, Miura AB . Fluorescence in situ hybridization of progenitor cells obtained by fluorescence-activated cell sorting for the detection of cells affected by chromosome abnormality trisomy 8 in patients with myelodysplastic syndromes Blood 1998 92: 2886–2892
Janssen JWG, Buschle M, Layton M, Drexler HG, Lyons J, van den Berghe H, Heimpel H, Kubanek B, Kleihauer E, Mufti GJ, Bartram CR . Clonal analysis of myelodysplastic sybdromes. Evidence for multipotent stem cell origin Blood 1989 73: 248–254
Acknowledgements
This work was supported in part by grants of the Deutsche Forschungsgemeinschaft (Ne 310/6–3), and the José Carreras Stiftung.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Brendel, C., Neubauer, A. Characteristics and analysis of normal and leukemic stem cells: current concepts and future directions. Leukemia 14, 1711–1717 (2000). https://doi.org/10.1038/sj.leu.2401907
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2401907
Keywords
This article is cited by
-
NF-κB-dependent DNA damage-signaling differentially regulates DNA double-strand break repair mechanisms in immature and mature human hematopoietic cells
Leukemia (2015)
-
Subsets of CD34+ and early engraftment kinetics in allogeneic peripheral SCT for AML
Bone Marrow Transplantation (2008)
-
CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance
Leukemia (2005)
-
Stem cells, aging, and cancer: inevitabilities and outcomes
Oncogene (2004)
-
Identification of precursors of leukemic dendritic cells differentiated from patients with acute myeloid leukemia
Leukemia (2002)