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

Autor: Parth C. Patel, Dinesh S. Rao, Jayanth Kumar Palanichamy, Norma I. Rodriguez-Malave, Jaime Anguiano, Kimanh T. Pioli, Tiffany M. Tran, Michael Davoren, Salemiz Sandoval, Thilini Fernando, Jorge R. Contreras, Michael O. Alberti
Rok vydání: 2015
Předmět:
MLL
Cancer Research
Microarray
Transcriptome
Mice
lncRNA
Stem Cell Research - Nonembryonic - Human
Gene expression
Gene Knockdown Techniques
Transcriptional regulation
2.1 Biological and endogenous factors
Aetiology
Cancer
Pediatric
Gene knockdown
Tumor
Leukemia
B-ALL
Hematology
3. Good health
Cell biology
Oncology
Molecular Medicine
RNA
Long Noncoding
Long Noncoding
Biotechnology
Pediatric Research Initiative
Cell Survival
Sp1 Transcription Factor
1.1 Normal biological development and functioning
Oncology and Carcinogenesis
Biology
Cell Line
Rare Diseases
Underpinning research
Cell Line
Tumor
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Genetics
Animals
Humans
Oncology & Carcinogenesis
Non-coding RNA
Gene
Cell Proliferation
Cell growth
Research
Hematopoietic Stem Cells
Stem Cell Research
Molecular biology
SP1
Gene expression profiling
RNA
Generic health relevance
Zdroj: Molecular cancer, vol 14, iss 1
Molecular Cancer
ISSN: 1476-4598
DOI: 10.1186/s12943-015-0485-z
Popis: 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. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0485-z) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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