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Involvement and functional impairment of the CD34(+)CD38(-)Thy-1(+) hematopoietic stem cell pool in myelodysplastic syndromes with trisomy 8.

Nilsson, Lars LU ; Åstrand-Grundström, Ingbritt LU ; Anderson, Kristina LU ; Arvidsson, Ingrid; Hokland, Peter; Bryder, David LU ; Kjeldsen, Lars; Johansson, Bertil LU ; Hellström-Lindberg, Eva and Hast, Robert, et al. (2002) In Blood 100(1). p.259-267
Abstract
Clonality studies of mature cells suggest that the primary transformation event in myelodysplastic syndrome (MDS) most frequently occurs in a myeloid-restricted progenitor, a hypothesis supported by recent studies of purified CD34(+)Thy1(+) hematopoietic stem cells (HSCs) in cases with trisomy 8 (+8). In contrast, we recently demonstrated that a lymphomyeloid 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... (More)
Clonality studies of mature cells suggest that the primary transformation event in myelodysplastic syndrome (MDS) most frequently occurs in a myeloid-restricted progenitor, a hypothesis supported by recent studies of purified CD34(+)Thy1(+) hematopoietic stem cells (HSCs) in cases with trisomy 8 (+8). In contrast, we recently demonstrated that a lymphomyeloid 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 nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice. Mixing experiments with normal CD34(+)CD38(-) cells suggested 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(+) HSCs, the secondary +8 event might frequently arise in progeny of MDS HSCs. Thus, CD34(+)CD38(-)Thy1(+) HSCs 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 HSCs, potentially complicating the development of autologous transplantation for MDS. (Less)
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Male, Human, Hematopoietic Stem Cells : pathology, Hematopoietic Stem Cells : immunology, Female, Clone Cells : pathology, Clone Cells : immunology, Pair 8, Chromosomes, Neoplastic : pathology, Cell Transformation, Neoplastic : genetics, Thy-1 : analysis, Antigens, Differentiation : analysis, CD34 : analysis, 80 and over, Aged, Middle Age, Myelodysplastic Syndromes : etiology, Myelodysplastic Syndromes : genetics, Myelodysplastic Syndromes : pathology, NAD+ Nucleosidase : analysis, Support, Non-U.S. Gov't, Trisomy, Tumor Stem Cells : immunology, Tumor Stem Cells : pathology
in
Blood
volume
100
issue
1
pages
259 - 267
publisher
American Society of Hematology
external identifiers
  • pmid:12070035
  • wos:000176477400036
  • scopus:0036659925
ISSN
1528-0020
DOI
10.1182/blood-2001-12-0188
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English
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33a7c40e-b1e4-4c83-a011-912fcee1199e (old id 108877)
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http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12070035&dopt=Abstract
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2007-07-24 09:21:21
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@article{33a7c40e-b1e4-4c83-a011-912fcee1199e,
  abstract     = {Clonality studies of mature cells suggest that the primary transformation event in myelodysplastic syndrome (MDS) most frequently occurs in a myeloid-restricted progenitor, a hypothesis supported by recent studies of purified CD34(+)Thy1(+) hematopoietic stem cells (HSCs) in cases with trisomy 8 (+8). In contrast, we recently demonstrated that a lymphomyeloid 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 nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice. Mixing experiments with normal CD34(+)CD38(-) cells suggested 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(+) HSCs, the secondary +8 event might frequently arise in progeny of MDS HSCs. Thus, CD34(+)CD38(-)Thy1(+) HSCs 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 HSCs, potentially complicating the development of autologous transplantation for MDS.},
  author       = {Nilsson, Lars and Åstrand-Grundström, Ingbritt and Anderson, Kristina and Arvidsson, Ingrid and Hokland, Peter and Bryder, David and Kjeldsen, Lars and Johansson, Bertil and Hellström-Lindberg, Eva and Hast, Robert and Jacobsen, Sten Eirik W},
  issn         = {1528-0020},
  keyword      = {Male,Human,Hematopoietic Stem Cells : pathology,Hematopoietic Stem Cells : immunology,Female,Clone Cells : pathology,Clone Cells : immunology,Pair 8,Chromosomes,Neoplastic : pathology,Cell Transformation,Neoplastic : genetics,Thy-1 : analysis,Antigens,Differentiation : analysis,CD34 : analysis,80 and over,Aged,Middle Age,Myelodysplastic Syndromes : etiology,Myelodysplastic Syndromes : genetics,Myelodysplastic Syndromes : pathology,NAD+ Nucleosidase : analysis,Support,Non-U.S. Gov't,Trisomy,Tumor Stem Cells : immunology,Tumor Stem Cells : pathology},
  language     = {eng},
  number       = {1},
  pages        = {259--267},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Involvement and functional impairment of the CD34(+)CD38(-)Thy-1(+) hematopoietic stem cell pool in myelodysplastic syndromes with trisomy 8.},
  url          = {http://dx.doi.org/10.1182/blood-2001-12-0188},
  volume       = {100},
  year         = {2002},
}