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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Lars Nilsson
  • Ingbritt Åstrand-Grundström
  • Kristina Anderson
  • Ingrid Arvidsson
  • Peter Hokland
  • David Bryder
  • Lars Kjeldsen
  • Bertil Johansson
  • Eva Hellström-Lindberg
  • Robert Hast
  • Sten Eirik W Jacobsen
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Hematology

Keywords

  • 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
Original languageEnglish
Pages (from-to)259-267
JournalBlood
Volume100
Issue number1
Publication statusPublished - 2002
Publication categoryResearch
Peer-reviewedYes