title: Enforced expression of E47 has differential effects on Lmo2-induced T-cell leukemias.
abstract: LIM domain only-2 (LMO2) overexpression in T cells induces leukemia but the molecular mechanism remains to be elucidated. In hematopoietic stem and progenitor cells, Lmo2 is part of a protein complex comprised of class II basic helix loop helix proteins, Tal1and Lyl1. The latter transcription factors heterodimerize with E2A proteins like E47 and Heb to bind E boxes. LMO2 and TAL1 or LYL1 cooperate to induce T-ALL in mouse models, and are concordantly expressed in human T-ALL. Furthermore, LMO2 cooperates with the loss of E2A suggesting that LMO2 functions by creating a deficiency of E2A. In this study, we tested this hypothesis in Lmo2-induced T-ALL cell lines. We transduced these lines with an E47/estrogen receptor fusion construct that could be forced to homodimerize with 4-hydroxytamoxifen. We discovered that forced homodimerization induced growth arrest in 2 of the 4 lines tested. The lines sensitive to E47 homodimerization accumulated in G1 and had reduced S phase entry. We analyzed the transcriptome of a resistant and a sensitive line to discern the E47 targets responsible for the cellular effects. Our results suggest that E47 has diverse effects in T-ALL but that functional deficiency of E47 is not a universal feature of Lmo2-induced T-ALL.
authors.affiliation: Departments of Cancer Biology and Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Charnise
authors.initials: C
authors.lastname: Goodings
authors.affiliation: Departments of Cancer Biology and Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Rati
authors.initials: R
authors.lastname: Tripathi
authors.affiliation: Departments of Cancer Biology and Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Cleveland
authors.affiliation: Departments of Cancer Biology and Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Natalina
authors.initials: N
authors.lastname: Elliott
authors.affiliation: Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.affiliation: Departments of Cancer Biology and Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: utpal.dave@vanderbilt.edu.
authors.forename: Utpal P
authors.initials: UP
authors.lastname: Davé
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism*; D015458:Leukemia, T-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055503:Protein Multimerization; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D058127:Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D060588:LIM Domain Proteins; D011518:Proto-Oncogene Proteins; D058127:Transcription Factor 3; C085117:LMO2 protein, human; C407909:TCF3 protein, human; C073366:TCF12 protein, human
keywords: E2A; LMO2; T-ALL; T-cell leukemia