title: LMO2 induces T-cell leukemia with epigenetic deregulation of CD4.
abstract: In this study, we present a remarkable clonal cell line, 32080, derived from a CD2-Lmo2- transgenic T-cell leukemia with differentiation arrest at the transition from the intermediate single positive to double positive stages of T-cell development. We observed that 32080 cells had a striking variegated pattern in CD4 expression. There was cell-to-cell variability, with some cells expressing no CD4 and others expressing high CD4. The two populations were isogenic and yet differed in their rates of apoptosis and sensitivity to glucocorticoid. We sorted the 32080 line for CD4-positive or CD4-negative cells and observed them in culture. After 1 week, both sorted populations showed variegated CD4 expression, like the parental line, showing that the two populations could interconvert. We determined that cell replication was necessary to transit from CD4(+) to CD4(-) and CD4(-) to CD4(+). Lmo2 knockdown decreased CD4 expression, while inhibition of intracellular NOTCH1 or histone deacetylase activity induced CD4 expression. Enforced expression of RUNX1 repressed CD4 expression. We analyzed the CD4 locus by Histone 3 chromatin immunoprecipitation and found silencing marks in the CD4(-) cells and activating marks in the CD4(+) population. The 32080 cell line is a striking model of intermediate single positive to double positive T-cell plasticity and invokes a novel mechanism for LMO2's oncogenic functions.
authors.affiliation: Tennessee Valley Healthcare System and the Vanderbilt University Medical Center, Departments of Medicine and Cancer Biology, Nashville, Tennessee, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Cleveland
authors.affiliation: Tennessee Valley Healthcare System and the Vanderbilt University Medical Center, Departments of Medicine and Cancer Biology, Nashville, Tennessee, USA.
authors.forename: Charnise
authors.initials: C
authors.lastname: Goodings
authors.affiliation: Tennessee Valley Healthcare System and the Vanderbilt University Medical Center, Departments of Medicine and Cancer Biology, Nashville, Tennessee, USA.
authors.forename: Rati M
authors.initials: RM
authors.lastname: Tripathi
authors.affiliation: Tennessee Valley Healthcare System and the Vanderbilt University Medical Center, Departments of Medicine and Cancer Biology, Nashville, Tennessee, USA.
authors.forename: Natalina
authors.initials: N
authors.lastname: Elliott
authors.affiliation: Vanderbilt University Medical Center, Department of Pathology, Microbiology, and Immunology, Nashville, Tennessee, USA.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Thompson
authors.affiliation: Center for Quantitative Sciences, Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Center for Quantitative Sciences, Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.affiliation: Tennessee Valley Healthcare System and the Vanderbilt University Medical Center, Departments of Medicine and Cancer Biology, Nashville, Tennessee, 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*; D000818:Animals; D015704:CD4 Antigens / Q000235:genetics*; D044127:Epigenesis, Genetic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D060588:LIM Domain Proteins / Q000235:genetics*; D015458:Leukemia, T-Cell / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015704:CD4 Antigens; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D011518:Proto-Oncogene Proteins