Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice.
New Zealand black (NZB) mice with autoimmune and B lymphoproliferative disease (B-LPD) are a model for human chronic lymphocytic leukemia (CLL). A genomewide linkage scan of the NZB loci associated with lymphoma was conducted in F1 backcrosses of NZB and a control strain, DBA/2. Of 202 mice phenotyped for the presence or absence of LPD, surface maker expression, DNA content, and microsatellite polymorphisms, 74 had disease. The CD5(+), IgM(+), B220(dim), hyperdiploid LPD was linked to 3 loci on chromosomes 14, 18, and 19 that are distinct from previously identified autoimmunity-associated loci. The region of synteny with mouse D14mit160 is the human 13q14 region, associated with human CLL, containing microRNAs mir-15a16-1. DNA sequencing of multiple NZB tissues identified a point mutation in the 3' flanking sequence of the identical microRNA, mir-16-1, and this mutation was not present in other strains, including the nearest neighbor, NZW. Levels of miR-16 were decreased in NZB lymphoid tissue. Exogenous miR-16 delivered to an NZB malignant B-1 cell line resulted in cell-cycle alterations and increased apoptosis. Linkage of the mir-15a/16-1 complex and the development of B-LPD in this spontaneous mouse model suggest that the altered expression of the mir-15a/16-1 is the molecular lesion in CLL.
Raveche
Elizabeth S
ES
Department of Pathology and Lab Medicine, University of Medicine and Dentistry New Jersey/New Jersey Medical School, Newark, NJ, USA.
Salerno
Erica
E
Scaglione
Brian J
BJ
Manohar
Vijaya
V
Abbasi
Fatima
F
Lin
Yi-Chu
YC
Fredrickson
Torgny
T
Landgraf
Pablo
P
Ramachandra
Sumant
S
Huppi
Konrad
K
Toro
Jorge R
JR
Zenger
Vincent E
VE
Metcalf
Robert A
RA
Marti
Gerald E
GE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001402:B-Lymphocytes; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics*; D033481:Chromosomes, Mammalian; D004247:DNA / Q000032:analysis; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008232:Lymphoproliferative Disorders / Q000235:genetics; D051379:Mice; D008814:Mice, Inbred NZB; D035683:MicroRNAs / Q000235:genetics* / Q000494:pharmacology; D017354:Point Mutation; D011110:Polymorphism, Genetic; D026801:Synteny / Q000235:genetics*
D035683:MicroRNAs; C522604:Mirn16 microRNA, mouse; D004247:DNA