Involvement and functional impairment of the CD34(+)CD38(-)Thy-1(+) hematopoietic stem cell pool in myelodysplastic syndromes with trisomy 8.
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.
Nilsson
Lars
L
Department of Stem Cell Biology, Lund University Hospital, Sweden.
Astrand-Grundström
Ingbritt
I
Anderson
Kristina
K
Arvidsson
Ingrid
I
Hokland
Peter
P
Bryder
David
D
Kjeldsen
Lars
L
Johansson
Bertil
B
Hellström-Lindberg
Eva
E
Hast
Robert
R
Jacobsen
Sten Eirik W
SE
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D018952:Antigens, CD34 / Q000032:analysis; D000943:Antigens, Differentiation / Q000032:analysis; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D002898:Chromosomes, Human, Pair 8; D002999:Clone Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000473:pathology*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D009244:NAD+ Nucleosidase / Q000032:analysis; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000473:pathology*; D018800:Thy-1 Antigens / Q000032:analysis; D014314:Trisomy
D015703:Antigens, CD; D018952:Antigens, CD34; D000943:Antigens, Differentiation; D008562:Membrane Glycoproteins; D018800:Thy-1 Antigens; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1