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Blood, Vol. 95 No. 3 (February 1), 2000:
pp. 1007-1013
NEOPLASIA
From the Departamento de Proliferación y Diferenciación
Celular, Instituto de Microbiología Bioquímica;
Servicio de Anatomía Patológica; and Servicio de
Hematología, Universidad de Salamanca, Salamanca, Spain.
BCR-ABL is a chimeric oncogene generated by
translocation of sequences from the chromosomal counterpart (c-ABL
gene) on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, BCR-ABLp190 and
BCR-ABLp210, are produced that are characteristic of
chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive
acute lymphoblastic leukemia (Ph1-ALL). In CML, the
transformation occurs at the level of pluripotent stem cells. However,
Ph1-ALL is thought to affect progenitor cells with lymphoid
differentiation. Here we demonstrate that the cell capable of
initiating human Ph1-ALL in non-obese diabetic mice with
severe combined immunodeficiency disease (NOD/SCID), termed SCID
leukemia-initiating cell (SL-IC), possesses the differentiative and
proliferative capacities and the potential for self-renewal expected of
a leukemic stem cell. The SL-ICs from all Ph1-ALL analyzed,
regardless of the heterogeneity in maturation characteristics of the
leukemic blasts, were exclusively CD34+
CD38
Acute leukemia derives from the clonal expansion of
hematopoietic precursors that have lost their capacity to proceed to
terminal differentiation. Leukemogenesis would therefore require the
accumulation of the minimum number of genetic events that result in
accelerated cell growth and differentiation block. A large number of
genetic alterations, including specific chromosome translocations, have been identified and causally linked to leukemogenesis, but the molecular basis of the composite leukemia phenotype remains largely unknown.1
A well-characterized example in the hematopoietic system involves the
rearrangements of the BCR and ABL genes in Philadelphia chromosome positive (Ph1+) chronic myelogenous leukemia
(CML) and acute lymphocytic leukemia (Ph1-ALL).2-11 Depending on the precise
breakpoint within the BCR gene, fusion proteins of 210 d (p210)
or 190 d (p190) are produced.2-11 The p210 and p190
BCR-ABL oncogenes contain identical ABL-derived sequences, respectively, but differ in the number of BCR-encoded amino
acid residues. The resulting oncoproteins, BCR-ABLp210 and
BCR-ABLp190, are required and sufficient for the malignant
transformation of hematopoietic cells.12
In CML, the transformation occurs at the level of pluripotent stem
cells.13 However, in most cases of Ph1-ALL,
which have a differentiated phenotype, the leukemogenic genetic defect
is believed to affect progenitor cells with lymphoid differentiation.14 These cases of Ph1-ALL
represent 30% of adult ALL cases, predominantly of B lineage, making
it the most frequently identified translocation in this group.15 Ph1-ALL is characterized by the
accumulation of large numbers of abnormal cells that fail to
differentiate into functional B lymphocytes.14,15 The
leukemic blasts have limited proliferative capacity, which suggests
that a small subpopulation of leukemic stem cells possess extensive
proliferative capacity and that the potential for self-renewal must
maintain the leukemia.15,16 Characterization of the
leukemic stem cells is fundamental in order to gain insight into the
composition of the leukemic clone and into the cellular and molecular
mechanisms that underlie leukemogenesis.
Because of the absence of a direct link between a cell carrying the
cytogenetic abnormality (BCR-ABLp190) and a
test of whether this cell has the capacity to maintain the disease in
vivo, 2 different hypotheses try to explain the link between the
BCR-ABLp190 oncogene and the
Ph1-ALL. One hypothesis suggests that many cell types in
the stem/progenitor hierarchy are susceptible to
transformation.14,17 The leukemogenic event would alter the
normal development program, thereby resulting in the expansion of
abnormal cells that are blocked at a particular stage of
differentiation. The degree of commitment of the target cell influences
the characteristics of the resulting leukemic blast cells. The second
hypothesis suggests that mutations responsible for transformation and
progression occur in primitive cells only.16 According to
this theory, the phenotype results from the ability of these primitive
leukemic stem cells to differentiate, depending on the influence of the
specific leukemogenic event. Resolution of this controversy is critical
in order to gain insight into the mechanism of oncogene action in
leukemic transformation and the design of new therapeutic strategies.
In this study we report that the cell capable of initiating human
Ph1-ALL in non-obese diabetic mice with severe combined
immunodeficiency disease (NOD/SCID), termed the SCID
leukemia-initiating cell (SL-IC), possesses differentiative and
proliferative capacities and has the potential for self-renewal
expected of a leukemic stem cell. The phenotype of SL-ICs was similar
to that of normal stem cells and was the same in every patient,
regardless of the lineage markers expressed by the leukemic blasts.
This indicates that normal primitive cells, rather than committed
progenitor cells, are the target for leukemic transformation in
Ph1-ALL.
Human cells
Animals and transplantation of Ph1-ALL cells into
NOD/SCID mice
Flow cytometric detection of human cells in murine tissues and sorting Bone marrow cells were flushed from the femurs and tibias of each mouse to be assessed using a syringe and a 26-gauge needle at indicated time points (4-8 weeks). Single-cell suspensions were then prepared by gentle aspiration. To prepare cells for flow cytometry, contaminated red blood cells were lysed with 8.3% ammonium chloride, and the remaining cells were then washed in phosphate-buffered saline (PBS) with 2% fetal calf serum (FCS) and 5% human serum to block fragment (Fc) receptors.
In vitro hematopoietic cell culture assays To support the formation of myeloid colonies, progenitors were cultured in an alpha-Modified Eagle Medium-based ( MEM-based) methylcellulose media (StemCell Technologies, Vancouver, BC, Canada) that was supplemented with 30% FBS, 1% bovine serum albumin, 2 mmol/L
L-glutamine, and 50 µmol/L 2-mercaptoethanol. Cytokines such as human
erythropoietin were added at the start of the culture. To examine
lymphoid colony formation, we used Iscove's Modified Dulbecco's
Medium-based (IMDM-based) methylcellulose (StemCell Technologies)
containing human IL-7 (10 ng/mL). All cultures were incubated at
37°C in a humidified chamber under 5% carbon dioxide. The
different categories of human colonies known to be generated under
either of these conditions were scored in situ after 2-3 weeks of
incubation at 37°C using well-established criteria. Duplicate plates were scored for each mouse. Leukemic blast colonies (20-100 cells) were scored at 7-8 days. The leukemic origin of the colonies was
confirmed by individually plucking each colony and examining the
immunophenotype. Only leukemic cells were detected from
normal clonogenic progenitors. Normal human progenitors were not
detected, even when cultures were left for an additional week. All
leukemic colonies contained the BCR-ABLp190 chromosome translocation.
Detection of the BCR-ABLp190 fusion gene product The BCR-ABLp190 product was detected by polymerase chain reaction (RT-PCR) using specific primers for both human BCR and ABL genes in engrafted NOD/SCID and control NOD/SCID mice and in vitro colonies. The specific BCR-ABLp190 fusion gene product was identified by hybridization with a specifc oligo spanning the gene fusion. The complementary DNA (cDNA) integrity was measured by hybridization of the RT-PCR product using actin specific primers with an internal actin human primer.DNA extraction and analysis High molecular weight DNA was isolated from the bone marrow of transplanted mice, EcoRI digests of genomic DNA (1 µg) were loaded into each lane, and the blots were hybridized with a human chromosome 17-specific-satellite probe (p17H8), as previously described.19 The proportion of human cells in each sample
was then inferred from the intensity of the characteristic 2.7 kilobase (kb) band obtained relative to those obtained on the same blot from a
series of artificial mixtures of human and mouse DNA (ranging from
0.1%-50% human DNA).
Development of the NOD/SCID leukemia model for Ph1-ALL Previous reports20-22 show that NOD/SCID mice are superior to other mouse strains for the engraftment of limiting cell doses or purified populations of normal human cells. The ability of NOD/SCID mice to become engrafted after the transplantation of lower cell doses and to regenerate higher numbers of very primitive human cells may be due, at least in part, to a reduced ability of NOD/SCID mice to eliminate foreign (xenogenic) cells, particularly when low numbers of cells are injected. Therefore, NOD/SCID mice are recipients of routine experimental studies of human hematopoiesis in an in vivo setting. To determine if NOD/SCID mice were optimal recipients for the engraftment of human Ph1-ALL cells, different cell doses were transplanted into NOD/SCID mice using standard procedures.23-25 The proportion of human cell engraftment in each sample was analyzed by Southern blot 4 to 6 weeks after transplant and then deduced from the intensity of the characteristic 2.7 kb band19 obtained on the same blot from a series of artificial mixtures of human and mouse DNA (Table 1). All samples from all patients were engrafted in the NOD/SCID mice to high levels (5%-100%). No normal human progenitors (defined by the absence of BCR-ABLp190) or cells with normal morphology were detected in the bone marrow of these mice (data not shown). This mouse model should therefore serve as a useful starting point for the further characterization of such Ph1-ALL cells in order to demonstrate the in vivo proliferative and developmental potential of transformed Ph1-ALL progenitors at various developmental stages.
Nature of the SL-ICs in Ph1-ALL In order to characterize the nature of the cell type that initiated the leukemic clone in transplanted NOD/SCID mice, we analyzed the cell-surface phenotype of SL-ICs from the different Ph1-ALL patients. We focused on surface markers such as CD34 and CD38 antigens because it has been shown that normal stem cells20-25 and AML-leukemic stem cells repopulating immunodeficient mice were exclusively CD34+ and CD38 .25,28-30 As was expected, there was
considerable heterogeneity from patient to patient in the expression of
CD34 and CD38 antigens in the Ph1-ALL samples (Table 1).
Ph1-ALL samples were first sorted into highly
purified CD34+ and CD34 cell fractions
that were injected at different cell doses into NOD/SCID mice. A
representative experiment from patient No. 2 is shown in Figure
1. In this sample, 90% of the original
blast population comprised CD34+ cell fractions. SL-ICs
were only present in the CD34+ fraction, and as few as
2 × 104 CD34+ cells were able to
initiate the proliferation of leukemic cells, whereas 100 times as many
CD34 cells did not engraft.
In vivo differentiative capacity of SL-ICs in Ph1-ALL
Clonogenic Ph1-ALL cells and resulting colonies in
methylcellulose cultures
Self-renewal capacity of SL-ICs assessed by serial transplantation Most leukemic blasts in Ph1-ALL have limited proliferative capacity and therefore must be constantly replenished by primitive cells capable of self-renewal. To determine whether SL-ICs have self-renewal potential, leukemic cells were transplanted serially into secondary recipients. As shown in Figure 3, all 3 samples could be successfully transplanted into secondary recipients with equivalent levels of human cell engraftment. The leukemic cell-surface phenotype was unchanged (data not shown). By the use of the quantitative SL-IC assay, the number of SL-ICs present in the donor sample and the primary NOD/SCID mouse was determined by densitometric analysis. For example, 8 mice were injected with 16 × 106 cells from patient No. 2. Since the frequency of SL-ICs in this sample was 12/106 cells (Table 1), each mouse was implanted with 192 SL-ICs. After 6 weeks, 1.2 × 108 pooled bone marrow cells from the 8 mice averaged 40% human cells as determined by densitometric analysis (Figure 3, lane 8). Taking into account that only 40% of the total bone marrow cells present in the mice were recovered, a total of 1.2 × 108 CD45+ cells were present in the bone marrow of these 8 mice. These CD45+ cells were sorted, and recipient secondary mice were injected with 2 × 105 cells. Because the mice injected with the 2 × 105 cells contained human cells (Figure 3, lane 9), the frequency of SL-ICs must be at least 1 SL-IC per 2 × 105 cells (or 600 per 1.2 × 108), which indicates that a minimum 80-fold expansion of SL-ICs must have occurred in the primary recipient. Similar calculations for the other 2 samples indicated a 40- to 100-fold expansion of SL-ICs. This calculation probably underestimates the SL-IC expansion because it assumes 100% recovery and does not account for efficiency of seeding to the recipient bone marrow.
SL-ICs in Ph1-ALL have the properties of stem cells We have characterized Ph1-ALL stem cells from samples of different patients on the basis of their ability to initiate human Ph1-ALL after transplantation of CD45+ sorted cells into NOD/SCID mice or SL-ICs. SL-ICs possessed 2 key criteria that define stem cells: (1) after transplantation, stem cells were able to proliferate and to differentiate, thereby producing a disease in mice which was identical to that in the donor, and (2) the stem cells were able to renew themselves, thereby enabling the reestablishment of Ph1-ALL in secondary recipient mice. The proliferative potential of SL-ICs is enormous, since millions of CD34++CD38 cells could be generated from
NOD/SCID recipients implanted with a single
CD34++CD38 SL-IC at limiting dilution.
Serial transplantation demonstrates that the SL-ICs are capable of
self-renewal for up to 8 weeks, thereby giving rise to a 30- to
100-fold expansion of the SL-IC pool in the primary transplanted
NOD/SCID recipient. Future studies will define whether the SL-ICs
continue to renew themselves for longer periods (for example, 9 months)
in primary recipients.
Human Ph1-ALL originated from primitive
CD34++CD38 fraction of all patient
samples regardless of the lineage markers expressed by the leukemic
blasts, the percentage of blast cells expressing the CD34 antigen, or
the FAB subtype. In this sense a recent report indicates that
engraftment of AML samples into NOD/SCID mice was also obtained
exclusively with CD34++CD38
cells.25 Thus, transformation at the level of
committed progenitors may be the exception rather than the rule.
Nevertheless, we cannot rule out the possibility that the target cell
is a committed progenitor cell with low CD38 expression or that the
particular cytokine combination used may have favored engraftment of
CD38 cells. Obviously, and in view of the finding
that some leukemias are present in utero,34 we cannot rule
out the possibility that the target cell could be a totipotent stem
cell. This possibility can now be explored using the new mouse models
made by homologous recombination.35
We are grateful to Dr J. Dick for providing the p17H8 probe.
Submitted June 23, 1999; accepted September 17, 1999.
Supported by grants BMH4-CT96-0375 from the European Commission and DGCYT (UE96-0041, PB96-0816, and 1FD97-0360); by grant FIS 99/0935 and from the Fundación Científica of the AECC (Madrid, Spain); by grant 1 R01 CA79 955-01 from the National Institutes of Health (Bethesda, MD); and by the Fundación Ferrer Investigación (C.C.).
C.C., N.G.-C., and J.P.-L. contributed equally to this work.
Reprints: I. Sánchez-García, Departamento de Proliferación y Diferenciación Celular, Instituto de Microbiología Bioquímica, CSIC/Universidad de Salamanca, Edificio Departamental, Avda del Campo Charro s/n, 37007 Salamanca, Spain; e-mail: isg{at}gugu.usal.es.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
1. Sánchez-García I. Consequences of chromosomal abnormalities in tumour development. Ann Rev Genet. 1997;31:429-453[Medline] [Order article via Infotrieve]. 2. Konopka JB, Watanabe SM, Witte ON. An alteration of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity. Cell. 1984;37:1035-1042[Medline] [Order article via Infotrieve]. 3. Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukemia. Nature. 1985;315:550-554[Medline] [Order article via Infotrieve].
4.
Mes-Masson AM, McLaughlin J, Daley GQ, Paskind M, Witte ON.
Overlapping cDNA clones define the complete coding region from the p210c-abl gene product associated with chronic myelogenous leukemia cells containing the Philadelphia chromosome.
Proc Natl Acad Sci U S A.
1986;83:9768-9772 5. Clark SS, McLaughlin J, Crist WM, Champlin R, Witte ON. Unique forms of the abl tyrosine kinase distinguish Ph1-Positive CML from Ph1-positive ALL. Science. 1987;35:85-88.
6.
Daley CG, McLaughlin J, Witte ON, Baltimore D.
The CML-specific p210 bcr/abl protein, unlike v-abl, does not transform NIH/3T3 fibroblasts.
Science.
1987;237:532-535 7. Hermans A, Heisterkamp N, von Linden M, et al. Unique forms of bcr and c-abl genes in Philadelphia chromosome positive acute lymphoblastic leukemia. Cell. 1987;51:33-40[Medline] [Order article via Infotrieve]. 8. Elefanty AG, Hariharan IK, Cory S. bcr-abl, the hallmark of chronic myeloid leukemia in man, induces multiple hemopoieitc neoplasms in mice. EMBO J. 1990;9:1069-1078[Medline] [Order article via Infotrieve]. 9. Heisterkamp N, Jenster G, Hoeve HT, Zovich D, Pattengale PK, Groffen J. Acute leukemia in bcr/abl transgenic mice. Nature. 1990;344:251-253[Medline] [Order article via Infotrieve].
10.
Kelliher MA, McLaughlin J, Witte ON, Rosenberg N.
Induction of chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL.
Proc Natl Acad Sci U S A.
1990;87:6649-6653
11.
Gishizhy ML, Johnson-White J, Witte ON.
Efficient transplantation of BCR-ABL-induced chronic myelogenous leukemia-like syndrome in mice.
Proc Natl Acad Sci U S A.
1993;90:3755-3759
12.
Sánchez-García I, Grütz G.
The tumorigenic activity of the BCR-ABL oncogenes is mediated by BCL-2.
Proc Natl Acad Sci U S A.
1995;92:5287-5291 13. Fialkow PJ. Clonal evolution of human myeloid leukemias. In: Bishop JM,Rowley JD,Greaves M, eds. Genes and Cancer. New York, NY: Liss; 1984:215-223.
14.
Cline MJ.
Mechanisms of disease: the molecular basis of leukemia.
N Engl J Med.
1994;330:328-336
15.
Copelan EA, McGuire EA.
The biology and treatment of acute lymphoblastic leukemia in adults.
Blood.
1995;85:1151-1168
16.
McCulloch E.
Stem cells in normal and leukemic hemopoiesis (Henry Stratton Lecture).
Blood.
1983;62:1-13 17. Barr FG. Translocations, cancer and the puzzle of specificity. Nature Genet. 1998;19:121-124[Medline] [Order article via Infotrieve]. 18. Bennett J, et al. Proposals for the classification of the acute leukemias. Br J Haematol. 1976;33:451-458[Medline] [Order article via Infotrieve]. 19. Lapidot T, Pflumio F, Doedens M, Murdoch B, Williams DE, Dick JE. Cytokine stimulation of multilineage hematopoiesis from immature human cells engrafted in SCID mice. Science 255: 1137-1141. 20. Lowry PA, Schultz LD, Greiner DL, et al. Improved engraftment of human cord blood stem cells in NOD/LtSz-scid/scid mice after irradiation or multiple-day injections into unirradiated recipients. Biol Blood Marrow Trans. 1996;2:15-21[Medline] [Order article via Infotrieve].
21.
Pflumio F, Izac B, Katz A, Shultz LD, Vainchenker W, Coulombel L.
Phenotype and function of human hematopoietic cells engrafting immune-deficient CB17-severe combined immunodeficiency mice and non-obese diabetic-severe combined immunodeficiency mice after transplantation of human cord blood mononuclear cells.
Blood.
1996;88:3731-3738
22.
Cashman JD, et al.
Kinetic evidence of the regeneration of multilineage hematopoiesis for primitive cells in normal human bone marrow transplanted into immunodeficient mice.
Blood.
1997;89:4307-4316 23. Larochelle A, Vormoor J, Janenberg H, et al. Identification of primitive hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: implications for gene therapy. Nature Med. 1996;2:1329-1337[Medline] [Order article via Infotrieve].
24.
Bhatia M, Wang J, Kapp U, Bonnet D, Dick J.
Purification of primitive human hematopoietic cells capable of repopulating NOD/SCID mice.
Proc Natl Acad Sci U S A.
1997;94:5320-5325 25. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoieitic cell. Nature Med. 1997;3:730-736[Medline] [Order article via Infotrieve].
26.
Wang J, Doedens M, Dick J.
Primitive human hematopoietic cells are enriched in cord blood compared to adult bone marrow or mobilized peripheral blood as measured by the quantitative in vivo SCID-repopulating cell (SRC) assay.
Blood.
1997;89:3919-3924 27. Traswell C. Limiting assays for the determination of immunocompetent cell frequencies. I. Data analysis. J. Immunol. 1981;126:1614-1619[Abstract]. 28. Civin C, Strauss LC, Brovall C, et al. Antigen 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[Abstract].
29.
Terstappen LWWM, Huang S, Safford M, Lansdorp PM, Loken MR.
Sequential generations of hematopoietic colonies derived from single nonlineage-committed CD34+CD38 30. Lapidot T, et al. A cell initiating human acute myeloid leukemia after transplantation into SCID mice. Nature. 1994;367:645-648[Medline] [Order article via Infotrieve].
31.
Suda T, et al.
A stimulatory effect of recombinant murine IL-7 on B-cell colony formation and an inhibitory effect of IL-1 32. Choo Y, Sánchez-García I, Klug A. In vivo repression by a site-specific DNA-binding protein designed against an oncogenic sequence. Nature. 1994;372:642-645[Medline] [Order article via Infotrieve].
33.
García Hernández B, Castellanos A, López A, Orfao A, Sánchez-García I.
Murine hematopoietic reconstitution after tagging and selection of retrovirally transduced bone marrow cells.
Proc Natl Acad Sci U S A.
1997;94:13,239-13,244
34.
Gale KB, et al.
Backtracking leukemia to birth: Identification of clonotypic gene fusion sequences in neonatal blood spots.
Proc Natl Acad Sci U S A.
1997;94:13,950-13,954
35.
Castellanos A, Pintado B, Weruaga E, et al.
Acute leukemia in chimeric mice by a bcr-ABLp190 fusion gene made by homologous recombination.
Blood.
1997;90:2168-2174 36. Fairbairn LJ, Cowling GJ, Reipert BM, Dexter TM. Suppression of apoptosis allows differentiation and development of a multipotent haematopoietic cell line in the absence of added growth factors. Cell. 1993;4:823-833. 37. García Hernández B, Sánchez-García I. Retroviral vector design for gene therapy of cancer: specific inhibition and tagging of BCR-ABLp190 cells. Mol Med. 1996;2:125-133.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|
 |
|
  H. Haeno, R. L. Levine, D. G. Gilliland, and F. Michor A progenitor cell origin of myeloid malignancies PNAS, September 29, 2009; 106(39): 16616 - 16621. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Heidenreich and J. Vormoor Malignant stem cells in childhood ALL: the debate continues! Blood, April 30, 2009; 113(18): 4476 - 4477. [Full Text] [PDF]
|
|
|
|
|
|
C. V. Cox, P. Diamanti, R. S. Evely, P. R. Kearns, and A. Blair Expression of CD133 on leukemia-initiating cells in childhood ALL Blood, April 2, 2009; 113(14): 3287 - 3296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ochi, H. Fujiwara, K. Suemori, T. Azuma, Y. Yakushijin, T. Hato, K. Kuzushima, and M. Yasukawa Aurora-A kinase: a novel target of cellular immunotherapy for leukemia Blood, January 1, 2009; 113(1): 66 - 74. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.-Y. Wang, F. Young, C.-Y. Chen, B. M. Stevens, S. J. Neering, R. M. Rossi, T. Bushnell, I. Kuzin, D. Heinrich, A. Bottaro, 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, November 15, 2008; 112(10): 4184 - 4192. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Michor Mathematical Models of Cancer Stem Cells J. Clin. Oncol., June 10, 2008; 26(17): 2854 - 2861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Wang, H. O'Leary, J. Fortney, and L. F. Gibson Ph+/VE-cadherin+ identifies a stem cell like population of acute lymphoblastic leukemia sustained by bone marrow niche cells Blood, November 1, 2007; 110(9): 3334 - 3344. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. V. Cox, H. M. Martin, P. R. Kearns, P. Virgo, R. S. Evely, and A. Blair Characterization of a progenitor cell population in childhood T-cell acute lymphoblastic leukemia Blood, January 15, 2007; 109(2): 674 - 682. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. T. Jordan, M. L. Guzman, and M. Noble Cancer stem cells. N. Engl. J. Med., September 21, 2006; 355(12): 1253 - 1261. [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Yuan, H. Yu, M. J. Boyer, X. Song, S. Cao, H. Shen, and T. Cheng Hematopoietic Stem Cells Are Not the Direct Target of Spontaneous Leukemic Transformation in p18INK4C-Null Reconstituted Mice Cancer Res., January 1, 2006; 66(1): 343 - 351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Du, N. A. Jenkins, and N. G. Copeland Insertional mutagenesis identifies genes that promote the immortalization of primary bone marrow progenitor cells Blood, December 1, 2005; 106(12): 3932 - 3939. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. Deasy, B. M. Gharaibeh, J. B. Pollett, M. M. Jones, M. A. Lucas, Y. Kanda, and J. Huard Long-Term Self-Renewal of Postnatal Muscle-derived Stem Cells Mol. Biol. Cell, July 1, 2005; 16(7): 3323 - 3333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Elrick, H. G. Jorgensen, J. C. Mountford, and T. L. Holyoake Punish the parent not the progeny Blood, March 1, 2005; 105(5): 1862 - 1866. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hotfilder, S. Rottgers, A. Rosemann, A. Schrauder, M. Schrappe, R. Pieters, H. Jurgens, J. Harbott, and J. Vormoor Leukemic Stem Cells in Childhood High-Risk ALL/t(9;22) and t(4;11) Are Present in Primitive Lymphoid-Restricted CD34+CD19- Cells Cancer Res., February 15, 2005; 65(4): 1442 - 1449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. V. Cox, R. S. Evely, A. Oakhill, D. H. Pamphilon, N. J. Goulden, and A. Blair Characterization of acute lymphoblastic leukemia progenitor cells Blood, November 1, 2004; 104(9): 2919 - 2925. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Harata, Y. Soda, K. Tani, J. Ooi, T. Takizawa, M. Chen, Y. Bai, K. Izawa, S. Kobayashi, A. Tomonari, et al. CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosome-positive acute lymphoblastic leukemia cells Blood, September 1, 2004; 104(5): 1442 - 1449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hotfilder, S. Rottgers, A. Rosemann, H. Jurgens, J. Harbott, and J. Vormoor Immature CD34+CD19- progenitor/stem cells in TEL/AML1-positive acute lymphoblastic leukemia are genetically and functionally normal Blood, June 28, 2002; 100(2): 640 - 646. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. George, J. Franklin, K. Kerkof, A. J. Shah, M. Price, E. Tsark, D. Bockstoce, D. Yao, N. Hart, S. Carcich, et al. Detection of leukemic cells in the CD34+CD38{-} bone marrow progenitor population in children with acute lymphoblastic leukemia Blood, June 15, 2001; 97(12): 3925 - 3930. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
progenitor cells.
Blood
1991;77:1218-1227