Myeloablative hematopoietic stem cell transplantation improves survival but is not curative in a pre-clinical model of myelodysplastic syndrome

• Published in: PloS one Vol. 12; no. 9; p. e0185219
• Main Authors: Chung, Yang Jo, Fry, Terry J, Aplan, Peter D
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.09.2017; Public Library of Science (PLoS)
• Subjects: Age; Animal models; Animals; Antigens; Biology and Life Sciences; Blood circulation; Bone marrow; Bone marrow transplantation; Cancer; Care and treatment; Cell survival; Comparative analysis; Disease control; Disease Models, Animal; Feasibility studies; Graft vs Host Disease - etiology; Graft vs Leukemia Effect - immunology; Graft-versus-host reaction; Hematopoietic stem cell transplantation; Hematopoietic Stem Cell Transplantation - adverse effects; Histocompatibility; Ionizing radiation; Irradiation; Leukemia; Leukocytes; Lymphocytes T; Medical research; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mortality; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - therapy; Patient outcomes; Peripheral blood; Physiological aspects; Radiation; Recurrence; Remission; Remission (Medicine); Remission Induction; Research and Analysis Methods; Rodents; Splenocytes; Stem cell transplantation; Stem cells; Survival; Survival Analysis; Syngeneic grafts; T-Lymphocytes, Regulatory - immunology; Transplantation; Transplantation Conditioning - adverse effects; Transplantation, Homologous; Transplants & implants; United States; United States > US; Maryland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0185219

Allogeneic hematopoietic stem cell transplantation (A-HSCT) remains the only curative option for patients with myelodysplastic syndrome (MDS). We used the NUP98-HOXD13 (NHD13) murine model for MDS to study HSCT in a pre-clinical setting. NHD13 recipients transplanted with syngeneic bone marrow (S-HSCT) following myeloablative irradiation showed disease remission, with normalization of peripheral blood parameters and marked decrease in circulating leukocytes derived from the MDS clone. Despite the disease remission and improved survival compared to non-transplanted NHD13 controls, all mice eventually relapsed, indicating persistence of a long-lived radio-resistant MDS clone. In an effort to induce a graft versus leukemia (GVL) effect, A-HSCT with donor bone marrow that was mismatched at minor histocompatibility loci was compared to S-HSCT. Although recipients in the A-HSCT showed a lower early relapse rate than in S-HSCT, all mice in both groups eventually relapsed and died by 54 weeks post-transplant. To obtain a more significant GVL effect, donor splenocytes containing reactive T-cells were transplanted with allogeneic bone marrow. Although the relapse rate was only 20% at post-transplantation week 38, suggesting a GVL effect, this was accompanied by a severe graft versus host disease (GVHD) Taken together, these findings indicate that a myeloablative dose of ionizing radiation is insufficient to eradicate the MDS initiating cell, and that transplantation of donor splenocytes leads to decreased relapse rates, at the cost of severe GVHD. We suggest that NHD13 mice represent a feasible pre-clinical model for the study of HSCT for MDS.