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Prepublished online as a Blood First Edition Paper on April 30, 2002; DOI 10.1182/blood-2001-12-0188.
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Blood, 1 July 2002, Vol. 100, No. 1, pp. 259-267
NEOPLASIA
Involvement and functional impairment of the
CD34+CD38 Thy-1+ hematopoietic
stem cell pool in myelodysplastic syndromes with trisomy 8
Lars Nilsson,
Ingbritt Åstrand-Grundström,
Kristina Anderson,
Ingrid Arvidsson,
Peter Hokland,
David Bryder,
Lars Kjeldsen,
Bertil Johansson,
Eva Hellström-Lindberg,
Robert Hast, and
Sten Eirik W. Jacobsen
From the Departments of Stem Cell Biology, Hematology,
and Clinical Genetics, Lund University Hospital, Sweden; the Divisions
of Hematology, Departments of Medicine, Karolinska Hospital and
Huddinge University Hospital, Karolinska Institutet, Stockholm,
Sweden; the Department of Hematology, Aarhus University Hospital,
Denmark; and the Department of Hematology, Rigshospitalet, Copenhagen,
Denmark.
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+CD38Thy1+ 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+CD38Thy-1+ HSCs, the
secondary +8 event might frequently arise in progeny of MDS HSCs.
Thus, CD34+CD38Thy1+ HSCs
are invariably part of the MDS clone also in +8 patients, and little
HSC activity can be recovered from the
CD34+ CD38Thy1+ 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.
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