title: TEL (ETV6)-AML1 (RUNX1) initiates self-renewing fetal pro-B cells in association with a transcriptional program shared with embryonic stem cells in mice.
abstract: The initial steps involved in the pathogenesis of acute leukemia are poorly understood. The TEL-AML1 fusion gene usually arises before birth, producing a persistent and covert preleukemic clone that may convert to precursor B cell leukemia following the accumulation of secondary genetic "hits." Here, we show that TEL-AML1 can induce persistent self-renewing pro-B cells in mice. TEL-AML1+ cells nevertheless differentiate terminally in the long term, providing a "window" period that may allow secondary genetic hits to accumulate and lead to leukemia. TEL-AML1-mediated self-renewal is associated with a transcriptional program shared with embryonic stem cells (ESCs), within which Mybl2, Tgif2, Pim2, and Hmgb3 are critical and sufficient components to establish self-renewing pro-B cells. We further show that TEL-AML1 increases the number of leukemia-initiating cells that are generated in collaboration with additional genetic hits, thus providing an overall basis for the development of novel therapeutic and preventive measures targeting the TEL-AML1-associated transcriptional program.
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan. stsuzuki@aichi-cc.jp
authors.forename: Shinobu
authors.initials: S
authors.lastname: Tsuzuki
authors.forename: Masao
authors.initials: M
authors.lastname: Seto
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000276:immunology; D053595:Embryonic Stem Cells / Q000276:immunology* / Q000473:pathology; D005333:Fetus; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D025765:HMGB3 Protein / Q000235:genetics / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000276:immunology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D018797:Cell Cycle Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D025765:HMGB3 Protein; D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; C499306:Mybl2 protein, mouse; C094167:Pim2 protein, mouse; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein; C505201:TG-interacting factor 2, mouse