Alterations in the mir-15a/16-1 Loci Impairs Its Processing and Augments B-1 Expansion in De Novo Mouse Model of Chronic Lymphocytic Leukemia (CLL)

Autor: Carol S. Lutz, Chingiz Underbayev, Gerald Marti, Steven R. Bauer, Heba Degheidy, Elizabeth Raveche, Siddha Kasar, Ilko K. Ilev, Moinuddin Hassan, Mona Batish
Rok vydání: 2016
Předmět:
0301 basic medicine
Lymphocytosis
Physiology
Chronic lymphocytic leukemia
medicine.disease_cause
Biochemistry
Hematologic Cancers and Related Disorders
Mice
Immune Physiology
Spectroscopy
Fourier Transform Infrared
Medicine and Health Sciences
RNA Processing
Post-Transcriptional
Side-Population Cells
Chronic Lymphoblastic Leukemia
Staining
B-Lymphocytes
Mutation
education.field_of_study
Multidisciplinary
Cell Staining
Animal Models
Hematology
Nucleic acids
Deletion Mutation
Oncology
Lymphoblastic Leukemia
Medicine
medicine.symptom
Research Article
Science
Molecular Sequence Data
Population
Congenic
Mouse Models
Biology
Research and Analysis Methods
Cell Line
03 medical and health sciences
Model Organisms
Transferases
Leukemias
microRNA
Genetics
medicine
Animals
Point Mutation
Allele
Non-coding RNA
education
Cell Proliferation
Base Sequence
Biology and life sciences
Point mutation
Proteins
Cancers and Neoplasms
medicine.disease
Leukemia
Lymphocytic
Chronic
B-Cell
Molecular biology
Gene regulation
Disease Models
Animal
MicroRNAs
030104 developmental biology
Genetic Loci
Specimen Preparation and Treatment
RNA
Gene expression
Spleen
Zdroj: PLoS ONE, Vol 11, Iss 3, p e0149331 (2016)
PLoS ONE
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0149331
Popis: New Zealand Black (NZB) mice, a de novo model of CLL, share multiple characteristics with CLL patients, including decreased expression of miR-15a/16-1. We previously discovered a point mutation and deletion in the 3' flanking region of mir-16-1 of NZB and a similar mutation has been found in a small number of CLL patients. However, it was unknown whether the mutation is the cause for the reduced miR-15a/16-1 expression and CLL development. Using PCR and in vitro microRNA processing assays, we found that the NZB sequence alterations in the mir-15a/16-1 loci result in deficient processing of the precursor forms of miR-15a/16-1, in particular, we observe impaired conversion of pri-miR-15a/16-1 to pre-miR-15a/16-1. The in vitro data was further supported by derivation of congenic strains with replaced mir-15a/16-1 loci at one or both alleles: NZB congenic mice (NmiR+/-) and DBA congenic mice (DmiR-/-). The level of miR-15a/16-1 reflected the configuration of the mir-15a/16-1 loci with DBA congenic mice (DmiR-/-) showing reduced miR-15a levels compared to homozygous wild-type allele, while the NZB congenic mice (NmiR+/-) showed an increase in miR-15a levels relative to homozygous mutant allele. Similar to Monoclonal B-cell Lymphocytosis (MBL), the precursor stage of the human disease, an overall expansion of the B-1 population was observed in DBA congenic mice (DmiR-/-) relative to wild-type (DmiR+/+). These studies support our hypothesis that the mutations in the mir-15a/16-1 loci are responsible for decreased expression of this regulatory microRNA leading to B-1 expansion and CLL development.
Databáze: OpenAIRE
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