Transplantation of a Myelodysplastic Syndrome by a Long-Term Repopulating Hematopoietic Cell

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-09, Vol.105 (37), p.14088-14093
• Main Authors: Chung, Yang Jo, Choi, Chul Won, Slape, Christopher, Fry, Terry, Aplan, Peter D.
• Format: Article
• Language: English
• Subjects: Animals; B lymphocytes; Biological Sciences; Blood cells; Blood diseases; Bone marrow; Bone Marrow - immunology; Cell Lineage; Cell Separation; Cells; Erythroid cells; Hematopoietic Stem Cell Transplantation; Hematopoietic System - cytology; Leukemia; Leukemia - pathology; Mice; Mice, Inbred C57BL; Myelodysplastic syndromes; Myelodysplastic Syndromes - pathology; Myelodysplastic Syndromes - surgery; Myeloid cells; Myeloid leukemia; Progenitor cells; Stem cell transplantation; Stem cells; Time Factors; Transplantation; Transplants & implants
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0804507105

The myelodysplastic syndromes (MDS) comprise a group of premalignant hematologic disorders characterized by ineffective hematopoiesis, dysplasia, and transformation to acute myeloid leukemia (AML). Although it is well established that many malignancies can be transplanted, there is little evidence to demonstrate that a premalignant disease entity, such as MDS or colonic polyps, can be transplanted and subsequently undergo malignant transformation in vivo. Using mice that express a NUP98-HOXD13 (NHD13) transgene in hematopoietic tissues, we show that a MDS can be transplanted to WT recipients. Recipients of the MDS bone marrow displayed all of the critical features of MDS, including peripheral blood cytopenias, dysplasia, and transformation to AML. Even when transplanted with a 10-fold excess of WT cells, the NHD13 cells outcompeted the WT cells over a 38-week period. Limiting-dilution experiments demonstrated that the frequency of the cell that could transmit the disease was ≈1/6,000-1/16,000 and that the MDS was also transferable to secondary recipients as a premalignant condition. Transformation to AML in primary transplant recipients was generally delayed (46-49 weeks after transplant); however, 6 of 10 secondary transplant recipients developed AML. These findings demonstrate that MDS originates in a transplantable, premalignant, long-term repopulating, MDS-initiating cell.