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

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.