The New Zealand black mouse as a model for the development and progression of chronic lymphocytic leukemia.
BACKGROUND
Similar to a subset of human patients who progress from monoclonal B lymphocytosis (MBL) to chronic lymphocytic leukemia (CLL), New Zealand Black (NZB) mice have an age-associated progression to CLL. The murine disease is linked to a genetic abnormality in microRNA mir-15a/16-1 locus, resulting in decreased mature miR-15a/16.


METHODS
Spleens of aging NZB were analyzed for the presence of B-1 cells via flow cytometry and for the presence of a side population (SP) via the ability of cells to exclude Hoechst 33342 dye. The SP was assayed for the presence of hyperdiploid B-1 clones and for the ability to differentiate into B-1 cells in vitro and transfer disease in vivo. In addition, enhanced apoptosis of chemoresistant NZB B-1 cells was examined by restoring miR-16 levels in nutlin-treated cells.


RESULTS
Aging NZB mice develop a B-1 expansion and clonal development that evolves from MBL into CLL. An expansion in SP is also seen. Although the SP did contain increased cells with stem cell markers, they lacked malignant B-1 cells and did not transfer disease in vivo. Similar to B-1 cells, splenic NZB SP also has decreased miR-15a/16 when compared with C57Bl/6. Exogenous addition of miR-15a/16 to NZB B-1 cells resulted in increased sensitivity to nutlin.


CONCLUSIONS
NZB serve as an excellent model for studying the development and progression of age-associated CLL. NZB SP cells do not seem to contain cancer stem cells, but rather the B-1 stem cell. NZB B-1 chemoresistance may be related to reduced miR-15a/16 expression.
Salerno
Erica
E
Department of Pathology and Lab Medicine, University of Medicine and Dentistry/New Jersey Medical School, Newark, New Jersey 07103, USA.
Yuan
Yao
Y
Scaglione
Brian J
BJ
Marti
Gerald
G
Jankovic
Alexander
A
Mazzella
Fermina
F
Laurindo
Maria Fernanda
MF
Despres
Daryl
D
Baskar
Sivasubramanian
S
Rader
Christoph
C
Raveche
Elizabeth
E
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002469:Cell Separation; D002470:Cell Survival; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D007093:Imidazoles / Q000494:pharmacology; D016130:Immunophenotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D010879:Piperazines / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology
D007093:Imidazoles; D010879:Piperazines; C482203:nutlin 1