title: Therapeutic implications of activation of the host gene (Dleu2) promoter for miR-15a/16-1 in chronic lymphocytic leukemia.
abstract: Genetic lesions and other regulatory events lead to silencing of the 13q14 locus in a majority of chronic lymphocytic leukemia (CLL) patients. This locus encodes a pair of critical proapoptotic microRNAs, miR-15a/16-1. Decreased levels of miR-15a/16-1 are critical for the increased survival exhibited by CLL cells. Similarly, in a de novo murine model of CLL, the NZB strain, germline-encoded regulation of the syntenic region resulted in decreased miR-15a/16-1. In this paper, we have identified additional molecular mechanisms regulating miR-15a/16-1 levels and have shown that the transcription factor BSAP (B-cell-specific activator protein) directly interacts with Dleu2, the host gene containing the miR-15a/16-1 loci, and by negative regulation of the Dleu2 promoter, results in repression of miR-15a/16-1 expression. CLL patient B-cell expression levels of BSAP were increased compared with control sources of B cells. With the use of small interfering RNA-mediated repression, the levels of BSAP were decreased in vitro in the NZB-derived malignant B-1 cell line, LNC, and in ex vivo CLL patient peripheral blood mononuclear cells (PBMCs). BSAP knockdown led to an increase in the expression of miR-15a/16-1 and an increase in apoptosis, and a cell cycle arrest in both the cell line and patient PBMCs. Moreover, using Dleu2 promoter analysis by chromatin immunoprecipitation assay, we have shown that BSAP directly interacts with the Dleu2 promoter. Derepression of the Dleu2 promoter via inhibition of histone deacetylation combined with BSAP knockdown increased miR-15a/16-1 expression, and also increased malignant B-cell death. In summary, therapy targeting enhanced host gene Dleu2 transcription may augment CLL therapy.
authors.affiliation: 1] New Jersey Medical School, Rutgers, Newark, NJ, USA [2].
authors.forename: S
authors.initials: S
authors.lastname: Kasar
authors.affiliation: New Jersey Medical School, Rutgers, Newark, NJ, USA.
authors.forename: C
authors.initials: C
authors.lastname: Underbayev
authors.affiliation: NIH, Bethesda, MD, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: New Jersey Medical School, Rutgers, Newark, NJ, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hanlon
authors.affiliation: New Jersey Medical School, Rutgers, Newark, NJ, USA.
authors.forename: S
authors.initials: S
authors.lastname: Aly
authors.affiliation: New Jersey Medical School, Rutgers, Newark, NJ, USA.
authors.forename: H
authors.initials: H
authors.lastname: Khan
authors.affiliation: 1] New Jersey Medical School, Rutgers, Newark, NJ, USA [2] Veterans Affairs New Jersey Health Care System, East Orange, NJ, USA.
authors.forename: V
authors.initials: V
authors.lastname: Chang
authors.affiliation: New Jersey Medical School, Rutgers, Newark, NJ, USA.
authors.forename: M
authors.initials: M
authors.lastname: Batish
authors.affiliation: New Jersey Medical School, Rutgers, Newark, NJ, USA.
authors.forename: T
authors.initials: T
authors.lastname: Gavrilova
authors.affiliation: New Jersey Medical School, Rutgers, Newark, NJ, USA.
authors.forename: F
authors.initials: F
authors.lastname: Badiane
authors.affiliation: OSEL/CDRH/FDA White Oak, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Degheidy
authors.affiliation: OSEL/CDRH/FDA White Oak, MD, USA.
authors.forename: G
authors.initials: G
authors.lastname: Marti
authors.affiliation: New Jersey Medical School, Rutgers, Newark, NJ, USA.
authors.forename: E
authors.initials: E
authors.lastname: Raveche
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D008814:Mice, Inbred NZB; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding; D014158:Transcription, Genetic; D014166:Transferases; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C109420:DLEU2 lncRNA, human; C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D062085:RNA, Long Noncoding; D025521:Tumor Suppressor Proteins; D014166:Transferases