Journal
MOLECULAR CANCER
Volume 14, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/s12943-015-0485-z
Keywords
lncRNA; B-ALL; MLL; SP1; Microarray; Leukemia; RNA; Non-coding RNA
Categories
Funding
- National Science Foundation [DGE-1144087]
- UCLA
- National Institute of Health (NIH) [T32 CA009056]
- institutional Tumor Immunology Training Grants [NIH T32CA009120, NIH T32009056]
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA Training Program
- Sidney Kimmel Translational Scholar Award [SKF-11-013]
- Irving Feintech Family Foundation/Tower Cancer Research Foundation Research Grant
- University of California Cancer Research Coordinating Committee
- Stein-Oppenheimer Endowment Award
- NIH [P01 HL073104, T32 HL086345]
- UCLA Broad Stem Cell Research Center (BSCRC)
- California Institute for Regenerative Medicine (CIRM) [TG2-01169]
- National Institutes of Health [CA-16042, AI-28697]
- JCCC
- UCLA AIDS Institute
- UCLA Council of Bioscience Resources
- David Geffen School of Medicine at UCLA
- [K08CA133521]
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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.
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