Long-term engraftment and clonal dominance of donor-derived del(20q) hematopoietic cells after allogeneic stem cell transplantation

In 1997, a 50-year-old woman who was retrospectively diagnosed with early asymptomatic myelodysplastic syndrome (MDS) served as a hematopoietic cell donor for her HLA-identical sister who had chemotherapy-refractory angioimmunoblastic T-cell lymphoma.¹  The preparative transplant regimen consisted of high-dose cyclophosphamide and fractionated total body irradiation; cyclosporine and methotrexate were given for graft-versus-host disease prophylaxis. The MDS of the donor was classified as refractory anemia (RA) and cytogenetically characterized by deletion of the long arm of chromosome 20 (del(20q)), which was detected by fluorescence in situ hybridization (FISH) in 18% and 24.5% of unfractionated marrow and blood mononuclear cells, respectively. Nevertheless, donor cell engraftment was timely and the patient developed mild graft-versus-host disease that promptly responded to therapy. As of July 2005, the patient was alive, clinically well, and in complete remission of her lymphoma. The patient's hematopoietic function after transplantation has been remarkable for thrombocytopenia and mild normocytic anemia without evidence for progression (February 2005: hemoglobin level, 118 g/L [11.8 g/dL]; platelet count, 55 × 10⁹/L; and absolute neutrophil count, 2.04 × 10⁹/L). Current clinical information about the stem cell donor was not available.

During the 7 years of posttransplantation follow-up, we analyzed donor cell engraftment in myeloid and lymphoid compartments of both blood and bone marrow using conventional cytogenetics, FISH, and variable number tandem repeats (VNTRs). Chimerism analysis by VNTRs confirmed 100% donor hematopoiesis in lymphoid and myeloid lineages by day 34 after transplantation, which has remained stable to date. Shortly after transplantation, at day 158, approximately 10% of granulocytes and monocytes in the blood carried the del(20q) abnormality; however, this population increased to represent 56% to 73% of blood myeloid cells by 3 and 7 years, respectively, after transplantation (Table 1). In addition, even though the del(20q) was not detectable in T cells (CD3⁺) or B cells (CD19⁺) at the time of engraftment, 16% of T cells and 26% of B cells were determined by FISH to be part of the abnormal clone at 7 years after transplantation.

These data indicate that after myeloablative conditioning, transplanted myelodysplastic donor cells with del(20q) could home to the marrow, proliferate efficiently, and differentiate. Furthermore, the abnormal clone contributed to long-term reconstitution of the recipient's hematopoietic system and, during 7 years of posttransplantation follow-up, emerged as dominant. Our data demonstrate that the 20q deletion in this patient arose in a multipotent progenitor cell capable of giving rise not only to myeloid cells, but also to B and T cells. While involvement of B cells in the myelodysplastic process has been reported,^2,3  MDS-specific cytogenetic markers in T cells are usually not detected.^3-5  This may be related to (1) preferential emergence of cytogenetic abnormalities in progenitors restricted to the myeloid lineage, (2) technical limitations to the detection of very small numbers of cytogenetically abnormal T cells, or (3) emergence of cytogenetic abnormalities that preferentially select against cells restricted to the T-cell lineage.²  Despite the anecdotal nature of this observation, it serves as a model to demonstrate the competitive advantage of cytogenetically abnormal, myelodysplastic hematopoietic stem and progenitor cells.