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Integrin-α9 overexpression underlies the niche-independent maintenance of leukemia stem cells in acute myeloid leukemia.
Niibori-Nambu, Akiko; Wang, Chelsia Qiuxia; Chin, Desmond Wai Loon; Chooi, Jing Yuan; Hosoi, Hiroki; Sonoki, Takashi; Tham, Cheng-Yong; Nah, Giselle Sek Suan; Cirovic, Branko; Tan, Darren Qiancheng; Takizawa, Hitoshi; Sashida, Goro; Goh, Yufen; Tng, Jiaqi; Fam, Wee Nih; Fullwood, Melissa Jane; Suda, Toshio; Yang, Henry; Tergaonkar, Vinay; Taniuchi, Ichiro; Li, Shang; Chng, Wee Joo; Osato, Motomi.
Afiliación
  • Niibori-Nambu A; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
  • Wang CQ; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Rese
  • Chin DWL; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • Chooi JY; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • Hosoi H; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan.
  • Sonoki T; Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan.
  • Tham CY; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • Nah GSS; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • Cirovic B; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
  • Tan DQ; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • Takizawa H; International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.
  • Sashida G; International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.
  • Goh Y; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • Tng J; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • Fam WN; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
  • Fullwood MJ; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
  • Suda T; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan; Institute of Hematology, Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical Co
  • Yang H; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • Tergaonkar V; Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
  • Taniuchi I; Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • Li S; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore.
  • Chng WJ; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; National University Cancer Institute, Singapore; National University Health System, Singapore. Electronic address: weejoo.chng@nus.edu.sg.
  • Osato M; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of General Internal Medicine, Kumamoto Kenhoku Hospital, Kumamoto, Japan. Electronic address: motokuma@k
Gene ; 928: 148761, 2024 Nov 30.
Article en En | MEDLINE | ID: mdl-39002785
ABSTRACT
Leukemia stem cells (LSCs) are widely believed to reside in well-characterized bone marrow (BM) niches; however, the capacity of the BM niches to accommodate LSCs is insufficient, and a significant proportion of LSCs are instead maintained in regions outside the BM. The molecular basis for this niche-independent behavior of LSCs remains elusive. Here, we show that integrin-α9 overexpression (ITGA9 OE) plays a pivotal role in the extramedullary maintenance of LSCs by molecularly mimicking the niche-interacting status, through the binding with its soluble ligand, osteopontin (OPN). Retroviral insertional mutagenesis conducted on leukemia-prone Runx-deficient mice identified Itga9 OE as a novel leukemogenic event. Itga9 OE activates Akt and p38MAPK signaling pathways. The elevated Myc expression subsequently enhances ribosomal biogenesis to overcome the cell integrity defect caused by the preexisting Runx alteration. The Itga9-Myc axis, originally discovered in mice, was further confirmed in multiple human acute myeloid leukemia (AML) subtypes, other than RUNX leukemias. In addition, ITGA9 was shown to be a functional LSC marker of the best prognostic value among 14 known LSC markers tested. Notably, the binding of ITGA9 with soluble OPN, a known negative regulator against HSC activation, induced LSC dormancy, while the disruption of ITGA9-soluble OPN interaction caused rapid cell propagation. These findings suggest that the ITGA9 OE increases both actively proliferating leukemia cells and dormant LSCs in a well-balanced manner, thereby maintaining LSCs. The ITGA9 OE would serve as a novel therapeutic target in AML.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Leucemia Mieloide Aguda Límite: Animals / Humans Idioma: En Revista: Gene Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Países Bajos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Leucemia Mieloide Aguda Límite: Animals / Humans Idioma: En Revista: Gene Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Países Bajos