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Involvement of Gpr125 in the myeloid sarcoma formation induced by cooperating MLL/AF10(OM-LZ) and oncogenic KRAS in a mouse bone marrow transplantation model.

Abstract
Oncogenic N-/KRAS mutations were frequently associated with MLL/AF10 in acute myeloid leukemia with myeloid sarcoma (MS). To study the cooperating leukemogenesis by MLL/AF10 and KRAS mutation, we retrovirally transduced MLL/AF10(OM-LZ) and KRASG12C into mouse bone marrow cells and generated two immortalized cell lines. The cells carrying cooperating MLL/AF10(OM-LZ) and KRASG12C had immature myelomonocytic phenotypes. Compared to a previously established cell line carrying MLL/AF10(OM-LZ) alone, cooperation of MLL/AF10(OM-LZ) with KRASG12C blocked the cells at a more immature myelomonocytic stage with reduced expression of monocyte/macrophage markers. The mice transplanted with the cells carrying cooperating MLL/AF10(OM-LZ) and KRASG12C, liked those transplanted with the cells carrying MLL/AF10(OM-LZ) alone, induced myeloproliferative disease-like myeloid leukemia, but in a shorter latency and formed multiple MS at the adipose tissues of skin, peritoneum and intraperitoneal cavity. Cooperation of MLL/AF10(OM-LZ) with KRASG12C increased cell adhesion via upregulation of an adhesion G-protein-coupled receptor Gpr125. Knockdown of Gpr125 in the cells by short hairpin RNA reduced cell aggregation and diminished MS formation in the transplanted mice. Our results indicated that upregulation of Gpr125 by cooperating MLL/AF10(OM-LZ) and KRASG12C promoted cell adhesion and contributed to the MS formation.
AuthorsJen-Fen Fu, Tzung-Hai Yen, Yu Chen, Ying-Jung Huang, Cheng-Lung Hsu, Der-Cherng Liang, Lee-Yung Shih
JournalInternational journal of cancer (Int J Cancer) Vol. 133 Issue 8 Pg. 1792-802 (Oct 15 2013) ISSN: 1097-0215 [Electronic] United States
PMID23564351 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 UICC.
Chemical References
  • GPR125 protein, mouse
  • Mllt10 protein, mouse
  • RNA, Small Interfering
  • Receptors, G-Protein-Coupled
  • Transcription Factors
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Kmt2a protein, mouse
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
Topics
  • Adolescent
  • Adult
  • Animals
  • Bone Marrow Transplantation
  • Cell Adhesion (genetics)
  • Cell Line, Tumor
  • Cell Lineage
  • Child
  • Child, Preschool
  • Disease Models, Animal
  • Female
  • Histone-Lysine N-Methyltransferase (genetics, metabolism)
  • Humans
  • Infant
  • Leukemia, Myeloid, Acute (metabolism)
  • Male
  • Mice
  • Middle Aged
  • Mutation
  • Myeloid-Lymphoid Leukemia Protein (genetics, metabolism)
  • Neoplasm Transplantation
  • Neoplasms, Adipose Tissue
  • Proto-Oncogene Proteins p21(ras) (genetics)
  • RNA Interference
  • RNA, Small Interfering
  • Receptors, G-Protein-Coupled (biosynthesis, genetics, metabolism)
  • Sarcoma, Myeloid (metabolism)
  • Transcription Factors (genetics, metabolism)
  • Up-Regulation
  • Young Adult

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