%0 Journal Article
%T Ets1 Plays a Critical Role in MLL/EB1-Mediated Leukemic Transformation in a Mouse Bone Marrow Transplantation Model
%A Jen-Fen Fu
%A Lee-Yung Shih
%A Tzung-Hai Yen
%A Ying-Jung Huang
%J Archive of "Neoplasia (New York, N.Y.)".
%D 2019
%R 10.1016/j.neo.2019.03.006
%X 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¨Cfour-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¨CPANTHER 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
%K aa
%K amino acid
%K ALL
%K acute lymphoblastic leukemia
%K AML
%K acute myeloid leukemia
%K AMoL
%K acute monocytic leukemia
%K APC
%K allophycocyanin
%K BD
%K DNA-binding domain
%K BM
%K bone marrow
%K CBC
%K complete blood cell
%K CC
%K coiled-coil
%K cDNA
%K complementary DNA
%K CFC
%K colony forming capacity
%K CTD
%K C-terminal domain
%K DAPI
%K 4¡ä
%K 6-diamidino-2-phenylindole
%K FHB
%K four-helix bundle
%K GM-CSF
%K granulocyte-monocyte colony stimulating factor
%K H&E
%K hematoxylin and eosin
%K IL
%K interleukin
%K ip
%K intraperitoneally
%K PB
%K peripheral blood
%K PBS
%K phosphate-buffered saline
%K PCR
%K polymerase chain reaction
%K PE
%K phycoerythrin
%K PI
%K propidium iodide
%K RT
%K reverse transcription
%K SCF
%K stem cell factor
%K shRNA
%K short hairpin RNA
%K WBC
%K white blood cell
%K 5-FU
%K 5-florouracil
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458341/