|
|
Prepublished online as a Blood First Edition Paper on April 30, 2002; DOI 10.1182/blood-2001-12-0188.
Submitted December 6, 2001
Accepted February 25, 2002
Involvement and functional impairment of the CD34+CD38-Thy-1+ hematopoietic stem cell pool in myelodysplastic syndromes with trisomy 8
Lars Nilsson, Ingbritt Astrand-Grundstrom, Kristina Anderson, Ingrid Arvidsson, Peter Hokland, David Bryder, Lars Kjeldsen, Bertil Johansson, Eva Hellstrom-Lindberg, Robert Hast, and Sten Eirik W Jacobsen*
Department of Stem Cell Biology, Lund University Hospital, Lund, Sweden; Department of Hematology, Lund University Hospital, Lund, Sweden
Division of Hematology, Dept. of Medicine, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden
Department of Hematology, Aarhus University Hospital, Aarhus, Sweden
Department of Stem Cell Biology, Lund University Hospital, Lund, Sweden
Department of Hematology, Rigshospitalet, Copenhagen, Denmark
Department of Clinical Genetics, Lund University Hospital, Lund, Denmark
Department of Medicine, Division of Hematology, Huddinge University, Karolinska Institutet, Stockholm, Sweden
* Corresponding author; email: sten.jacobsen{at}stemcell.lu.se.
Clonality studies of mature cells suggest that the primary transformation event in MDS most frequently occurs in a myeloid-restricted progenitor, a hypothesis supported by recent studies of purified CD34+Thy1+ hematopoietic stem cells (HSC) in cases with trisomy 8 (+8). In contrast, we recently demonstrated that a lympho-myeloid HSC is the target for transformation in MDS cases with del(5q), potentially reflecting heterogeneity within MDS. However, since +8 is known to frequently be a late event in the MDS transformation process, it remained a possibility that CD34+CD38-Thy1+ HSC disomic for chromosome 8 might be part of the MDS clone. In the present studies, although a variable fraction of CD34+CD38-(Thy1+) cells were disomic for chromosome 8, they did not possess normal HSC activity in long-term cultures and NOD-SCID mice. Mixing experiments with normal CD34+CD38- cells demonstrated that this HSC deficiency was intrinsic and not mediated by indirect mechanisms. Furthermore, investigation of 4 MDS cases with combined del(5q) and +8, demonstrated that the +8 aberration was always secondary to del(5q). Whereas del(5q) invariably occurs in CD34+CD38-Thy-1+ HSC, the secondary +8 event might frequently arise in progeny of MDS HSC. Thus, CD34+CD38-Thy1+ HSC are invariably part of the MDS clone also in +8 patients, and little HSC activity can be recovered from the CD34+CD38-Thy1+ HSC. Finally, in advanced cases of MDS, the MDS reconstituting activity is exclusively derived from the minor CD34+CD38- HSC population, demonstrating that MDS stem cells have a similar phenotype as normal HSC, potentially complicating the development of autologous transplantation for MDS.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
D. T. Starczynowski, S. Vercauteren, A. Telenius, S. Sung, K. Tohyama, A. Brooks-Wilson, J. J. Spinelli, C. J. Eaves, A. C. Eaves, D. E. Horsman, et al.
High-resolution whole genome tiling path array CGH analysis of CD34+ cells from patients with low-risk myelodysplastic syndromes reveals cryptic copy number alterations and predicts overall and leukemia-free survival
Blood,
October 15, 2008;
112(8):
3412 - 3424.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Grovdal, R. Khan, A. Aggerholm, P. Antunovic, J. Astermark, P. Bernell, L.-M. Engstrom, L. Kjeldsen, O. Linder, L. Nilsson, et al.
Negative Effect of DNA Hypermethylation on the Outcome of Intensive Chemotherapy in Older Patients with High-Risk Myelodysplastic Syndromes and Acute Myeloid Leukemia following Myelodysplastic Syndrome
Clin. Cancer Res.,
December 1, 2007;
13(23):
7107 - 7112.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Nilsson, P. Eden, E. Olsson, R. Mansson, I. Astrand-Grundstrom, B. Strombeck, K. Theilgaard-Monch, K. Anderson, R. Hast, E. Hellstrom-Lindberg, et al.
The molecular signature of MDS stem cells supports a stem-cell origin of 5q myelodysplastic syndromes
Blood,
October 15, 2007;
110(8):
3005 - 3014.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Huff, W. Matsui, B. D. Smith, and R. J. Jones
The paradox of response and survival in cancer therapeutics
Blood,
January 15, 2006;
107(2):
431 - 434.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Sternberg, S. Killick, T. Littlewood, C. Hatton, A. Peniket, T. Seidl, S. Soneji, J. Leach, D. Bowen, C. Chapman, et al.
Evidence for reduced B-cell progenitors in early (low-risk) myelodysplastic syndrome
Blood,
November 1, 2005;
106(9):
2982 - 2991.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Tehranchi, B. Fadeel, J. Schmidt-Mende, A.-M. Forsblom, E. Emanuelsson, M. Jadersten, B. Christensson, R. Hast, R. B. Howe, J. Samuelsson, et al.
Antiapoptotic Role of Growth Factors in the Myelodysplastic Syndromes: Concordance Between In vitro and In vivo Observations
Clin. Cancer Res.,
September 1, 2005;
11(17):
6291 - 6299.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. B. Kerbauy, V. Lesnikov, B. Torok-Storb, E. Bryant, and H. J. Deeg
Engraftment of distinct clonal MDS-derived hematopoietic precursors in NOD/SCID-{beta}2-microglobulin-deficient mice after intramedullary transplantation of hematopoietic and stromal cells
Blood,
October 1, 2004;
104(7):
2202 - 2203.
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Thanopoulou, J. Cashman, T. Kakagianne, A. Eaves, N. Zoumbos, and C. Eaves
Engraftment of NOD/SCID-{beta}2 microglobulin null mice with multilineage neoplastic cells from patients with myelodysplastic syndrome
Blood,
June 1, 2004;
103(11):
4285 - 4293.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. J. Jones, W. H. Matsui, and B. D. Smith
Cancer Stem Cells: Are We Missing the Target?
J Natl Cancer Inst,
April 21, 2004;
96(8):
583 - 585.
[Full Text]
[PDF]
|
|
|
|
|
