2007 Fiscal Year Final Research Report Summary
Developmental mechanisms of hematological malignancies revealed by humanized mouse models.
| Project/Area Number |
17390281
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Kyushu University |
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Principal Investigator |
HARADA Mine Kyushu University, Faculty of Medicine, Visiting researcher (00019621)
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| Co-Investigator(Kenkyū-buntansha) |
SHIMODA Kazuya Miyazaki University, Faculty of Medicine, Professor (90311844)
NAGAFUJI Koji Kyushu University, Hospital, Assistant Professor (60343323)
HARADA Naoki Kyushu University, Hospital, Assistant Professor (80404028)
石川 文彦 九州大学, 大学院・医学研究院, 共同研究員 (30403918)
TAKENAKA Katsuto Kyushu University, Hospital, Assistant Professor (30301295)
TAKENAKA Katsuto Kyushu University, Faculty of Medicine, Visiting researcher (30301295)
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| Project Period (FY) |
2005 – 2007
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| Keywords | chronic myelocytic leukemia / human T cell leukemia / myelofibrosis / accelerated phase / transgenic mouse |
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| Research Abstract |
Idiopathic myelofibrosis (IMF) is characterized by clonal proliferation of abnormal myelomonocytic cells and megakaryocytes These cells are thought to secrete various cytokines resulting in reactive fibrosis and Increased collagen content in the bone marrow (BM) and the fibrotic changes in the BM leads to extramedullary hematopoiesis and increased frequency of CD34+ cells in the peripheral blood (PB) Although IMF is thought to originate from an abnormality at the level of hematopoietic stem cell (HSC), this has not been experimentally addressed using primary human IMF samples Tb demonstrate the involvement of HSCs in the pathogenesis of IMF and to establish an in vivo model of IMT, we employed the newborn NOD / SCID/IL2rg-null xenotransplantation model that efficiently supports engraftment of normal and malignant human stem cells We purified PB CD334+ cells and PB CD34 + CD38- cells from six IMF patents, and intravenously transplanted the purified cells into newborn NOD/SCID/IL2rg-null
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recipients In long-term observation of the recipient mice, we analyzed human CD45+ hematopoietic cell chimerism both in the PB and in the BM, suppression of murine normal hematopoiesis, and the fibrotic changes in the BM, Six out of thirteen recipients transplanted with patient HSCs exhibited human hematopoietic engraftment, and CD33+ myeloid cells accounted for 80.5%+ / 9.41% of all the engrafted CD45+ population (as compared with the recipients transplanted with normal HSCs) BM of all engrafted recipients demonstrated fibrotic changes associated with increased proliferation of fibroblasts and the presence of human megakaryocytes, recapitulating the clinical features of IMF In the 7 remaining recipients, PB hCD45 chimerism was < 15% at thirty-two weeks and decreased over time and fibroblast proliferation could not be demonstrated in the BM at forty weeks To investigate the origin of BM fibroblast, we performed FISH analysis using human and mouse centromeric probes and immuno-staining using anti CD45 and anti-vimentin antibodies Of sixty fibroblasts examined, fifty-four cells were of human origin. These findings demonstrate that the IMF initiating cells are contained within the CD34+ CD38-fraction and these cells possess differentiation capacity to fibroblasts The newborn NOD/SCID/IL2rg-null xenotransplantation model provides an in vivo model of primary human IMF that may lead to better understanding of the mechanisms of IMF pathogenesis including the identification of IMF stem cell and the development of novel therapeutic agents for IMF. Less
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Research Products
(78 results)
