BALR-6 regulates cell growth and cell survival in B-lymphoblastic leukemia

Molecular Cancer

Research

Michael J. Davoren¹  Kimanh T. Pioli²  Parth C. Patel²  Thilini R. Fernando²  Jaime Anguiano²  Tiffany M. Tran²  Michael O. Alberti²  Salemiz Sandoval²  Jayanth Kumar Palanichamy³  Jorge R. Contreras⁴  Norma I. Rodríguez-Malavé⁴  Dinesh S. Rao⁵  Gay M. Crooks⁵ 

[1] Department of Environmental Health Sciences, UCLA, Los Angeles, USA;Molecular Toxicology Interdepartmental Ph.D. Program, UCLA, Los Angeles, USA;Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA;Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA;All India Institute of Medical Sciences (AIIMS), New Delhi, India;Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA;Cellular and Molecular Pathology Ph.D. Program, UCLA, Los Angeles, USA;Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA;Cellular and Molecular Pathology Ph.D. Program, UCLA, Los Angeles, USA;Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, USA;Broad Stem Cell Research Center, UCLA, 650 Charles E. Young Drive, Factor 12-272, 90095, Los Angeles, CA, USA;

关键词: lncRNA;    B-ALL;    MLL;    SP1;    Microarray;    Leukemia;    RNA;    Non-coding RNA;   

DOI  :  10.1186/s12943-015-0485-z

 received in 2015-07-25, accepted in 2015-12-11,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundA 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.ResultsHere, 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.ConclusionsOur 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.

【 授权许可】

CC BY   
© Rodríguez-Malavé et al. 2015