title: BALR-6 regulates cell growth and cell survival in B-lymphoblastic leukemia.
abstract: BACKGROUND
  A new class of non-coding RNAs, known as long non-coding RNAs (lncRNAs), has been recently described. These lncRNAs are implicated to play pivotal roles in various molecular processes, including development and oncogenesis. Gene expression profiling of human B-ALL samples showed differential lncRNA expression in samples with particular cytogenetic abnormalities. One of the most promising lncRNAs identified, designated B-ALL associated long RNA-6 (BALR-6), had the highest expression in patient samples carrying the MLL rearrangement, and is the focus of this study.
  
  
  RESULTS
  Here, we performed a series of experiments to define the function of BALR-6, including several novel splice forms that we identified. Functionally, siRNA-mediated knockdown of BALR-6 in human B-ALL cell lines caused reduced cell proliferation and increased cell death. Conversely, overexpression of BALR-6 isoforms in both human and mouse cell lines caused increased proliferation and decreased apoptosis. Overexpression of BALR-6 in murine bone marrow transplantation experiments caused a significant increase in early hematopoietic progenitor populations, suggesting that its dysregulation may cause developmental changes. Notably, the knockdown of BALR-6 resulted in global dysregulation of gene expression. The gene set was enriched for leukemia-associated genes, as well as for the transcriptome regulated by Specificity Protein 1 (SP1). We confirmed changes in the expression of SP1, as well as its known interactor and downstream target CREB1. Luciferase reporter assays demonstrated an enhancement of SP1-mediated transcription in the presence of BALR-6. These data provide a putative mechanism for regulation by BALR-6 in B-ALL.
  
  
  CONCLUSIONS
  Our findings support a role for the novel lncRNA BALR-6 in promoting cell survival in B-ALL. Furthermore, this lncRNA influences gene expression in B-ALL in a manner consistent with a function in transcriptional regulation. Specifically, our findings suggest that BALR-6 expression regulates the transcriptome downstream of SP1, and that this may underlie the function of BALR-6 in B-ALL.
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA. nirodriguez@mednet.ucla.edu.|Cellular and Molecular Pathology Ph.D. Program, UCLA, Los Angeles, USA. nirodriguez@mednet.ucla.edu.
authors.forename: Norma I
authors.initials: NI
authors.lastname: Rodríguez-Malavé
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA. trfernando@mednet.ucla.edu.
authors.forename: Thilini R
authors.initials: TR
authors.lastname: Fernando
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA. pcpatel@mednet.ucla.edu.
authors.forename: Parth C
authors.initials: PC
authors.lastname: Patel
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA. jrcontreras@mednet.ucla.edu.|Cellular and Molecular Pathology Ph.D. Program, UCLA, Los Angeles, USA. jrcontreras@mednet.ucla.edu.
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Contreras
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA. drjayanth@aiims.edu.|All India Institute of Medical Sciences (AIIMS), New Delhi, India. drjayanth@aiims.edu.
authors.forename: Jayanth Kumar
authors.initials: JK
authors.lastname: Palanichamy
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA. ttran@mednet.ucla.edu.
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Tran
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA. janguiano@mednet.ucla.edu.
authors.forename: Jaime
authors.initials: J
authors.lastname: Anguiano
authors.affiliation: Department of Environmental Health Sciences, UCLA, Los Angeles, USA. mdavoren@g.ucla.edu.|Molecular Toxicology Interdepartmental Ph.D. Program, UCLA, Los Angeles, USA. mdavoren@g.ucla.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Davoren
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA. malberti@mednet.ucla.edu.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Alberti
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA. kpioli@mednet.ucla.edu.
authors.forename: Kimanh T
authors.initials: KT
authors.lastname: Pioli
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA. salemizsandoval@mednet.ucla.edu.
authors.forename: Salemiz
authors.initials: S
authors.lastname: Sandoval
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA. gcrooks@mednet.ucla.edu.|Cellular and Molecular Pathology Ph.D. Program, UCLA, Los Angeles, USA. gcrooks@mednet.ucla.edu.|Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, USA. gcrooks@mednet.ucla.edu.|Broad Stem Cell Research Center, UCLA, 650 Charles E. Young Drive, Factor 12-272, Los Angeles, CA, 90095, USA. gcrooks@mednet.ucla.edu.
authors.forename: Gay M
authors.initials: GM
authors.lastname: Crooks
authors.affiliation: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA. drao@mednet.ucla.edu.|Cellular and Molecular Pathology Ph.D. Program, UCLA, Los Angeles, USA. drao@mednet.ucla.edu.|Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, USA. drao@mednet.ucla.edu.|Broad Stem Cell Research Center, UCLA, 650 Charles E. Young Drive, Factor 12-272, Los Angeles, CA, 90095, USA. drao@mednet.ucla.edu.
authors.forename: Dinesh S
authors.initials: DS
authors.lastname: Rao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D055785:Gene Knockdown Techniques; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D051379:Mice; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000502:physiology; D059467:Transcriptome
chemical_list: C000610444:BALR-6 non-coding RNA, human; D062085:RNA, Long Noncoding; D016329:Sp1 Transcription Factor