Abstract
MLL/AF4 and AML/MTG8 represent two leukemic fusion genes, which are most frequently found in infant acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), respectively. We examined the influence of MLL/AF4 and AML1/MTG8 fusion genes on the expression of TERT coding for the telomerase protein subunit, and subsequently telomerase activity in t(4;11)-positive ALL and t(8;21)-positive cell lines, respectively. MLL/AF4 suppression diminished telomerase activity and expression of TERT. Blocking pro-apoptotic caspase activation in conjunction with MLL/AF4 knockdown enhanced the inhibition of TERT gene expression, which suggests that MLL/AF4 depletion does not reduce TERT expression levels by inducing apoptosis. Knockdown of HOXA7, a direct transcriptional target of MLL/AF4 fusion gene, caused a reduction of telomerase and TERT to an extent similar to that observed with MLL/AF4 suppression. Chromatin immunoprecipitation of SEM cells, using ectopically expressed FLAG-tagged Hoxa7, indicates HOXA7 binding site in the TERT promoter region. Furthermore, suppression of the AML1/MTG8 fusion gene was associated with severely reduced clonogenicity, induction of replicative senescence, impaired TERT expression and accelerated telomere shortening. We thus present findings that show a mechanistic link between leukemic fusion proteins, essential for development and maintenance of leukemia, and telomerase, a key element of both normal and malignant self-renewal.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis
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Blotting, Western
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Cellular Senescence
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Chromatin Immunoprecipitation
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Chromosomes, Human, Pair 11 / genetics
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Chromosomes, Human, Pair 21 / genetics
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Chromosomes, Human, Pair 4 / genetics
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Chromosomes, Human, Pair 8 / genetics
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Core Binding Factor Alpha 2 Subunit / antagonists & inhibitors
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Core Binding Factor Alpha 2 Subunit / genetics*
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Core Binding Factor Alpha 2 Subunit / metabolism
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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In Situ Hybridization, Fluorescence
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Myeloid-Lymphoid Leukemia Protein / antagonists & inhibitors
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Myeloid-Lymphoid Leukemia Protein / genetics*
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Myeloid-Lymphoid Leukemia Protein / metabolism
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Oncogene Proteins, Fusion / antagonists & inhibitors
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Oncogene Proteins, Fusion / genetics*
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Oncogene Proteins, Fusion / metabolism
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology*
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RNA, Messenger / genetics
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RNA, Small Interfering / pharmacology
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RUNX1 Translocation Partner 1 Protein
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Reverse Transcriptase Polymerase Chain Reaction
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Telomerase / genetics*
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Telomerase / metabolism
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Telomere / genetics
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Translocation, Genetic
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Tumor Cells, Cultured
Substances
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AML1-ETO fusion protein, human
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Core Binding Factor Alpha 2 Subunit
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HOXA7 protein, human
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Homeodomain Proteins
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MLL-AF4 fusion protein, human
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Oncogene Proteins, Fusion
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RNA, Messenger
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RNA, Small Interfering
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RUNX1 Translocation Partner 1 Protein
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Myeloid-Lymphoid Leukemia Protein
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TERT protein, human
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Telomerase