Ets1 Plays a Critical Role in MLL/EB1-Mediated Leukemic Transformation in a Mouse Bone Marrow Transplantation Model
| Autor: | Ying-Jung Huang, Jen-Fen Fu, Tzung-Hai Yen, Lee-Yung Shih |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research BD DNA-binding domain Myeloid Oncogene Proteins Fusion Cellular differentiation CFC colony forming capacity Cell CBC complete blood cell Apoptosis Small hairpin RNA FHB four-helix bundle Mice PCR polymerase chain reaction 0302 clinical medicine APC allophycocyanin hemic and lymphatic diseases Acute monocytic leukemia AML acute myeloid leukemia Bone Marrow Transplantation RT reverse transcription Gene Expression Regulation Leukemic Cell Differentiation lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens CTD C-terminal domain Leukemia Cell Transformation Neoplastic medicine.anatomical_structure GM-CSF granulocyte-monocyte colony stimulating factor AMoL acute monocytic leukemia 030220 oncology & carcinogenesis Leukemia Monocytic Acute shRNA short hairpin RNA ip intraperitoneally Microtubule-Associated Proteins Myeloid-Lymphoid Leukemia Protein WBC white blood cell Original article aa amino acid PBS phosphate-buffered saline macromolecular substances Biology PB peripheral blood lcsh:RC254-282 CC coiled-coil Leukemogenic PI propidium iodide Proto-Oncogene Protein c-ets-1 cDNA complementary DNA 03 medical and health sciences medicine Animals neoplasms Cell Proliferation Leukemia Experimental SCF stem cell factor Gene Expression Profiling Histone-Lysine N-Methyltransferase PE phycoerythrin ALL acute lymphoblastic leukemia medicine.disease IL interleukin Mice Inbred C57BL Transplantation Disease Models Animal 030104 developmental biology BM bone marrow H&E hematoxylin and eosin NIH 3T3 Cells Cancer research 5-FU 5-florouracil DAPI 4′ 6-diamidino-2-phenylindole |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 21, Iss 5, Pp 469-481 (2019) Neoplasia (New York, N.Y.) |
| ISSN: | 1476-5586 |
| Popis: | Leukemogenic potential of MLL fusion with the coiled-coil domain-containing partner genes and the downstream target genes of this type of MLL fusion have not been clearly investigated. In this study, we demonstrated that the coiled-coil–four-helix bundle structure of EB1 that participated in the MLL/EB1 was required for immortalizing mouse bone marrow (BM) cells and producing myeloid, but not lymphoid, cell lines. Compared to MLL/AF10, MLL/EB1 had low leukemogenic ability. The MLL/EB1 cells grew more slowly owing to increased apoptosis in vitro and induced acute monocytic leukemia with an incomplete penetrance and longer survival in vivo. A comparative analysis of transcriptome profiling between MLL/EB1 and MLL/AF10 cell lines revealed that there was an at least two-fold difference in the induction of 318 genes; overall, 51.3% (163/318) of the genes were known to be bound by MLL, while 15.4% (49/318) were bound by both MLL and MLL/AF9. Analysis of the 318 genes using Gene Ontology–PANTHER overrepresentation test revealed significant differences in several biological processes, including cell differentiation, proliferation/programmed cell death, and cell homing/recruitment. The Ets1 gene, bound by MLL and MLL/AF9, was involved in several biological processes. We demonstrated that Ets1 was selectively upregulated by MLL/EB1. Short hairpin RNA knockdown of Ets1 in MLL/EB1 cells reduced the expression of CD115, apoptosis rate, competitive engraftment to BM and spleen, and incidence of leukemia and prolonged the survival of the diseased mice. Our results demonstrated that MLL/EB1 upregulated Ets1, which controlled the balance of leukemia cells between apoptosis and BM engraftment/clonal expansion. Novelty and impact of this study The leukemogenic potential of MLL fusion with cytoplasmic proteins containing coiled-coil dimerization domains and the downstream target genes of this type of MLL fusion remain largely unknown. Using a retroviral transduction/transplantation mouse model, we demonstrated that MLL fusion with the coiled-coil–four-helix bundle structure of EB1 has low leukemogenic ability; Ets1, which is upregulated by MLL/EB1, plays a critical role in leukemic transformation by balance between apoptosis and BM engraftment/clonal expansion. |
| Databáze: | OpenAIRE |
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