title: Establishment of a humanized APL model via the transplantation of PML-RARA-transduced human common myeloid progenitors into immunodeficient mice.
abstract: Recent advances in cancer biology have revealed that many malignancies possess a hierarchal system, and leukemic stem cells (LSC) or leukemia-initiating cells (LIC) appear to be obligatory for disease progression. Acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia characterized by the formation of a PML-RARα fusion protein, leads to the accumulation of abnormal promyelocytes. In order to understand the precise mechanisms involved in human APL leukemogenesis, we established a humanized in vivo APL model involving retroviral transduction of PML-RARA into CD34(+) hematopoietic cells from human cord blood and transplantation of these cells into immunodeficient mice. The leukemia well recapitulated human APL, consisting of leukemic cells with abundant azurophilic abnormal granules in the cytoplasm, which expressed CD13, CD33 and CD117, but not HLA-DR and CD34, were clustered in the same category as human APL samples in the gene expression analysis, and demonstrated sensitivity to ATRA. As seen in human APL, the induced APL cells showed a low transplantation efficiency in the secondary recipients, which was also exhibited in the transplantations that were carried out using the sorted CD34- fraction. In order to analyze the mechanisms underlying APL initiation and development, fractionated human cord blood was transduced with PML-RARA. Common myeloid progenitors (CMP) from CD34(+)/CD38(+) cells developed APL. These findings demonstrate that CMP are a target fraction for PML-RARA in APL, whereas the resultant CD34(-) APL cells may share the ability to maintain the tumor.
authors.affiliation: Research Center for Cancer Stem Cell, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Medical Research Institute, Tokai University, Isehara, Kanagawa, Japan; Department of Laboratory Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Matsushita
authors.affiliation: Research Center for Cancer Stem Cell, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Medical Research Institute, Tokai University, Isehara, Kanagawa, Japan; Department of Cell Transplantation, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yahata
authors.affiliation: Research Center for Cancer Stem Cell, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Yin
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: Research Center for Cancer Stem Cell, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Research Center for Cancer Stem Cell, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Muguruma
authors.affiliation: Research Center for Cancer Stem Cell, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Support Center for Medical Research and Education, Tokai University, Isehara, Kanagawa, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Matsuzawa
authors.affiliation: Support Center for Medical Research and Education, Tokai University, Isehara, Kanagawa, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Support Center for Medical Research and Education, Tokai University, Isehara, Kanagawa, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Support Center for Medical Research and Education, Tokai University, Isehara, Kanagawa, Japan.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Laboratory Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Anar
authors.initials: A
authors.lastname: Damdinsuren
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Onizuka
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ito
authors.affiliation: Department of Laboratory Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Miyachi
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.affiliation: Research Center for Cancer Stem Cell, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Medical Research Institute, Tokai University, Isehara, Kanagawa, Japan; Division of Hematology and Oncology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002454:Cell Differentiation; D004195:Disease Models, Animal; D005312:Fetal Blood / Q000166:cytology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000401:mortality / Q000473:pathology*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D014183:Transplantation, Heterologous
chemical_list: D018952:Antigens, CD34; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D017493:Leukocyte Common Antigens