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Leukemia. 2015 Mar;29(3):606-14. doi: 10.1038/leu.2014.239. Epub 2014 Aug 8.

In vitro expansion of CD34(+)CD38(-) cells under stimulation with hematopoietic growth factors on AGM-S3 cells in juvenile myelomonocytic leukemia.

Author information

1
Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.
2
Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
3
Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
4
1] Department of Pediatric Hematology/Oncology, Research Hospital, Institute of Medical Science, University of Tokyo, Minato-ku, Japan [2] Division of Stem Cell Processing, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Japan.
5
1] Division of Stem Cell Processing, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Japan [2] Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, China.
6
Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.
7
1] Department of Pediatric Hematology/Oncology, Research Hospital, Institute of Medical Science, University of Tokyo, Minato-ku, Japan [2] Division of Stem Cell Processing, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Japan [3] Department of Pediatrics, Shinshu Ueda Medical Center, National Hospital Organization, Ueda, Japan.

Abstract

Using serum-containing culture, we examined whether AGM-S3 stromal cells, alone or in combination with hematopoietic growth factor(s), stimulated the proliferation of CD34(+) cells from patients with juvenile myelomonocytic leukemia (JMML). AGM-S3 cells in concert with stem cell factor plus thrombopoietin increased the numbers of peripheral blood CD34(+) cells to approximately 20-fold of the input value after 2 weeks in nine JMML patients with either PTPN11 mutations or RAS mutations, who received allogeneic hematopoietic transplantation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) also augmented the proliferation of JMML CD34(+) cells on AGM-S3 cells. The expansion potential of CD34(+) cells was markedly low in four patients who achieved spontaneous hematological improvement. A large proportion of day-14-cultured CD34(+) cells were negative for CD38 and cryopreservable. Cultured JMML CD34(+)CD38(-) cells expressed CD117, CD116, c-mpl, CD123, CD90, but not CXCR4, and formed GM and erythroid colonies. Day-7-cultured CD34(+) cells from two of three JMML patients injected intrafemorally into immunodeficient mice stimulated with human GM-CSF after transplantation displayed significant hematopoietic reconstitution. The abilities of OP9 cells and MS-5 cells were one-third and one-tenth, respectively, of the value obtained with AGM-S3 cells. Our culture system may provide a useful tool for elucidating leukemogenesis and for therapeutic approaches in JMML.

PMID:
25102944
DOI:
10.1038/leu.2014.239
[Indexed for MEDLINE]

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