Noriyuki Saito1,2, Takuji Yamauchi1, Noriaki Kawano3, Rintaro Ono4, Shuro Yoshida5, Toshihiro Miyamoto1, Tomohiko Kamimura6, Leonard D Shultz7, Yoriko Saito4, Katsuto Takenaka8, Kazuya Shimoda9, Mine Harada10, Koichi Akashi11, Fumihiko Ishikawa12. 1. Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. 2. Department of Hematology, Saiseikai Fukuoka General Hospital, 1-3-46 Tenjin, Chuo-ku, Fukuoka, 810-0001, Japan. 3. Department of Internal Medicine, Miyazaki Prefectural Miyazaki Hospital, Miyazaki, Japan. 4. Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 5. Department of Hematology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan. 6. Division of Hematology, Harasanshin Hospital, Fukuoka, Japan. 7. The Jackson Laboratory, Bar Harbor, ME, USA. 8. Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Ehime, Japan. 9. Division of Hematology, Diabetes, and Endocrinology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. 10. Karatsu Higashimatsuura Medical Center, Karatsu, Japan. 11. Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. akashi@med.kyushu-u.ac.jp. 12. Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. fumihiko.ishikawa@riken.jp.
Abstract
INTRODUCTION: Primary myelofibrosis (PMF) is a clonal stem cell disorder characterized by myeloid dominant hematopoiesis and dysregulated proliferation of fibroblasts in the bone marrow. However, how these aberrant myeloid cells and fibroblasts are produced remains unclear. AIM AND METHODS: In this study, we examined in vivo engraftment kinetics of PMF patient-derived CD34+ cells in immunecompromised NOD/SCID/IL2rgKO (NSG) mice. Engrafted human cells were analyzed with flow cytometry, and proliferation of fibroblastic cells and bone marrow fibrosis were assessed with the histo-pathological examination. RESULTS: Transplantation of PMF patient-derived circulating CD34+ fractions into NSG newborns recapitulates clinical features of human PMF. Engraftment of human CD45+ leukocytes resulted in anemia and myeloid hyperplasia accompanied by bone marrow fibrosis by six months post-transplantation. Fibrotic bone marrow contained CD45-vimentin+ cells of both human and mouse origin, suggesting that circulating malignant CD34+ subsets contribute to myelofibrotic changes in PMF through direct and indirect mechanisms. CONCLUSION: A patient-derived xenotransplantation (PDX) model of PMF allows in vivo examination of disease onset and propagation originating from immature CD34+ cells and will support the investigation of pathogenesis and development of therapeutic modalities for the disorder.
INTRODUCTION: Primary myelofibrosis (PMF) is a clonal stem cell disorder characterized by myeloid dominant hematopoiesis and dysregulated proliferation of fibroblasts in the bone marrow. However, how these aberrant myeloid cells and fibroblasts are produced remains unclear. AIM AND METHODS: In this study, we examined in vivo engraftment kinetics of PMF patient-derived CD34+ cells in immunecompromised NOD/SCID/IL2rgKO (NSG) mice. Engrafted human cells were analyzed with flow cytometry, and proliferation of fibroblastic cells and bone marrow fibrosis were assessed with the histo-pathological examination. RESULTS: Transplantation of PMF patient-derived circulating CD34+ fractions into NSG newborns recapitulates clinical features of human PMF. Engraftment of human CD45+ leukocytes resulted in anemia and myeloid hyperplasia accompanied by bone marrow fibrosis by six months post-transplantation. Fibrotic bone marrow contained CD45-vimentin+ cells of both human and mouse origin, suggesting that circulating malignant CD34+ subsets contribute to myelofibrotic changes in PMF through direct and indirect mechanisms. CONCLUSION: A patient-derived xenotransplantation (PDX) model of PMF allows in vivo examination of disease onset and propagation originating from immature CD34+ cells and will support the investigation of pathogenesis and development of therapeutic modalities for the disorder.
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