title: Identification of cooperative genes for E2A-PBX1 to develop acute lymphoblastic leukemia.
abstract: E2A-PBX1 is a chimeric gene product detected in t(1;19)-bearing acute lymphoblastic leukemia (ALL) with B-cell lineage. To investigate the leukemogenic process, we generated conditional knock-in (cKI) mice for E2A-PBX1, in which E2A-PBX1 is inducibly expressed under the control of the endogenous E2A promoter. Despite the induced expression of E2A-PBX1, no hematopoietic disease was observed, strongly suggesting that additional genetic alterations are required to develop leukemia. To address this possibility, retroviral insertional mutagenesis was used. Virus infection efficiently induced T-cell, B-cell, and biphenotypic ALL in E2A-PBX1 cKI mice. Inverse PCR identified eight retroviral common integration sites, in which enhanced expression was observed in the Gfi1, Mycn, and Pim1 genes. In addition, it is of note that viral integration and overexpression of the Zfp521 gene was detected in one tumor with B-cell lineage; we previously identified Zfp521 as a cooperative gene with E2A-HLF, another E2A-involving fusion gene with B-lineage ALL. The cooperative oncogenicity of E2A-PBX1 with overexpressed Zfp521 in B-cell tumorigenesis was indicated by the finding that E2A-PBX1 cKI, Zfp521 transgenic compound mice developed B-lineage ALL. Moreover, upregulation of ZNF521, the human counterpart of Zfp521, was found in several human leukemic cell lines bearing t(1;19). These results indicate that E2A-PBX1 cooperates with additional gene alterations to develop ALL. Among them, enhanced expression of ZNF521 may play a clinically relevant role in E2A fusion genes to develop B-lineage ALL.
authors.affiliation: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sera
authors.affiliation: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Norimasa
authors.initials: N
authors.lastname: Yamasaki
authors.affiliation: Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Oda
authors.affiliation: Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Nagamachi
authors.affiliation: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Wolff
authors.affiliation: Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inukai
authors.affiliation: Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Inaba
authors.affiliation: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Honda
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D006801:Humans; D051379:Mice; D016254:Mutagenesis, Insertional; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C472572:Evi3 protein, mouse; C407909:TCF3 protein, human; C083400:PBX1 protein, human; C529598:zinc finger protein 521, human
keywords: Acute lymphoblastic leukemia; E2A-PBX1; Zfp521/ZNF521; conditional knock-in mice; retroviral insertional mutagenesis