期刊
BLOOD
卷 130, 期 4, 页码 397-407出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-01-763219
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资金
- Aplastic Anemia and MDS International Foundation
- Lauri Strauss Leukemia Foundation
- Leukemia and Lymphoma Society Special Fellow Award
- American Society of Hematology Senior Research Training Award for Fellows
- New York State Council on Graduate Medical Education Empire Clinical Research Investigator Program Fellowship
- Moffitt Cancer Center
- American Society of Hematology
- Edward P. Evans Foundation
- Department of Defense Bone Marrow Failure Research Program [BM150092, W81XWH-12-1-0041]
- National Institutes of Health, National Heart, Lung, and Blood Institute [R01 HL128239]
- Josie Robertson Investigator Program
- Starr Foundation [I8-A8-075]
- Leukemia and Lymphoma Society
- Pershing Square Sohn Cancer Research Alliance
- CDMRP [BM150092, 893251] Funding Source: Federal RePORTER
Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap disorders characterized by monocytosis, myelodysplasia, and a characteristic hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Currently, there are no available disease-modifying therapies for CMML, nor are there preclinical models that fully recapitulate the unique features of CMML. Through use of immunocompromised mice with transgenic expression of human GM-CSF, interleukin-3, and stem cell factor in a NOD/SCID-IL2R gamma(null) background (NSGS mice), we demonstrate remarkable engraftment of CMML and JMML providing the first examples of serially transplantable and genetically accurate models of CMML. Xenotransplantation of CD34(+) cells (n = 8 patients) or unfractionated bone marrow (BM) or peripheral blood mononuclear cells (n 5 10) resulted in robust engraftment of CMML in BM, spleen, liver, and lung of recipients (n = 82 total mice). Engrafted cells were myeloid-restricted and matched the immunophenotype, morphology, and genetic mutations of the corresponding patient. Similar levels of engraftment were seen upon serial transplantation of human CD34(+) cells in secondary NSGS recipients (2/5 patients, 6/11mice), demonstrating the durability of CMML grafts and functionally validating CD34(+) cells as harboring the disease-initiating compartment in vivo. Successful engraftments of JMML primary samples were also achieved in all NSGS recipients (n 5 4 patients, n 5 12 mice). Engraftment of CMML and JMML resulted in overt phenotypic abnormalities and lethality in recipients, which facilitated evaluation of the JAK2/FLT3 inhibitor pacritinib in vivo. These data reveal that NSGS mice support the development of CMML and JMML disease-initiating and mature leukemic cells in vivo, allowing creation of genetically accurate preclinical models of these disorders.
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