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Myelodysplasia after clonal hematopoiesis with APOBEC3-mediated CYBB inactivation in retroviral gene therapy for X-CGD.
Uchiyama, Toru; Kawai, Toshinao; Nakabayashi, Kazuhiko; Nakazawa, Yumiko; Goto, Fumihiro; Okamura, Kohji; Nishimura, Toyoki; Kato, Koji; Watanabe, Nobuyuki; Miura, Akane; Yasuda, Toru; Ando, Yukiko; Minegishi, Tomoko; Edasawa, Kaori; Shimura, Marika; Akiba, Yumi; Sato-Otsubo, Aiko; Mizukami, Tomoyuki; Kato, Motohiro; Akashi, Koichi; Nunoi, Hiroyuki; Onodera, Masafumi.
Afiliação
  • Uchiyama T; Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan. Electronic address: uchiyama-t@ncchd.go.jp.
  • Kawai T; Division of Immunology, National Center for Child Health and Development, Tokyo, Japan.
  • Nakabayashi K; Department of Maternal-Fetal Biology, National Center for Child Health and Development, Tokyo, Japan.
  • Nakazawa Y; Division of Immunology, National Center for Child Health and Development, Tokyo, Japan.
  • Goto F; Division of Immunology, National Center for Child Health and Development, Tokyo, Japan.
  • Okamura K; Department of Systems BioMedicine, National Center for Child Health and Development, Tokyo, Japan.
  • Nishimura T; Division of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
  • Kato K; Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.
  • Watanabe N; Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan.
  • Miura A; Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan.
  • Yasuda T; Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan.
  • Ando Y; Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan.
  • Minegishi T; Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan.
  • Edasawa K; Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan.
  • Shimura M; Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan.
  • Akiba Y; Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan.
  • Sato-Otsubo A; Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Pediatric Hematology and Oncology, National Center for Child Health and Development, Tokyo, Japan.
  • Mizukami T; Department of Pediatrics, NHO Kumamoto Medical Center, Kumamoto, Japan.
  • Kato M; Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Pediatric Hematology and Oncology, National Center for Child Health and Development, Tokyo, Japan.
  • Akashi K; Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.
  • Nunoi H; Division of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
  • Onodera M; Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan.
Mol Ther ; 31(12): 3424-3440, 2023 Dec 06.
Article em En | MEDLINE | ID: mdl-37705244
ABSTRACT
Stem cell gene therapy using the MFGS-gp91phox retroviral vector was performed on a 27-year-old patient with X-linked chronic granulomatous disease (X-CGD) in 2014. The patient's refractory infections were resolved, whereas the oxidase-positive neutrophils disappeared within 6 months. Thirty-two months after gene therapy, the patient developed myelodysplastic syndrome (MDS), and vector integration into the MECOM locus was identified in blast cells. The vector integration into MECOM was detectable in most myeloid cells at 12 months after gene therapy. However, the patient exhibited normal hematopoiesis until the onset of MDS, suggesting that MECOM transactivation contributed to clonal hematopoiesis, and the blast transformation likely arose after the acquisition of additional genetic lesions. In whole-genome sequencing, the biallelic loss of the WT1 tumor suppressor gene, which occurred immediately before tumorigenesis, was identified as a potential candidate genetic alteration. The provirus CYBB cDNA in the blasts contained 108 G-to-A mutations exclusively in the coding strand, suggesting the occurrence of APOBEC3-mediated hypermutations during the transduction of CD34-positive cells. A hypermutation-mediated loss of oxidase activity may have facilitated the survival and proliferation of the clone with MECOM transactivation. Our data provide valuable insights into the complex mechanisms underlying the development of leukemia in X-CGD gene therapy.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Síndromes Mielodisplásicas / Doença Granulomatosa Crônica Limite: Adult / Humans Idioma: En Revista: Mol Ther Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Síndromes Mielodisplásicas / Doença Granulomatosa Crônica Limite: Adult / Humans Idioma: En Revista: Mol Ther Ano de publicação: 2023 Tipo de documento: Article