Murine models of chronic lymphocytic leukaemia: role of microRNA‐16 in the New Zealand Black mouse model

Abstract

SummaryMouse models are valuable tools in the study of human chronic lymphocytic leukaemia (CLL). The New Zealand Black (NZB) strain is a naturally occurring model of late-onset CLL characterized by B-cell hyperproliferation and autoimmunity early in life, followed by progression to CLL. Other genetically engineered models of CLL that have been developed include (NZB · NZW) F1 mice engineered to express IL5, mice expressing human TCL1A, and mice overexpressing both BCL2 and a tumour necrosis factor receptor-associated factor. The applicability to human CLL varies with each model, suggesting that CLL is a multifactorial disease. Our work with the de novo NZB model has revealed many similarities to the human situation, particularly familial CLL. In NZB, the malignant clones express CD5, zap-70, and have chromosomal instability and germline Ig sequence. We also identified a point mutation in the 3¢-flanking sequence of Mirn16-1, which resulted in decreased levels of the microRNA, miR-16 in lymphoid tissue. Exogenous restoration of miR-16 to an NZB malignant B-1 cell line resulted in cell cycle alterations, suggesting that the altered expression of Mirn15a/16-1 is an important molecular lesion in CLL. Future studies utilizing the NZB mouse could ascertain the role of environmental triggers, such as low dose radiation and organic chemicals in the augmentation of a pre-existing propensity to develop CLL.Keywords: mouse models of chronic lymphocytic leukaemia, New Zealand Black, microRNA.The development of chronic lymphocytic leukaemia (CLL) in humans is believed to be polygenetic, exhibiting the highest incidence of familial leukaemia, yet emerging from many factors (Ishibe et al, 2001;Caporaso et al, 2004;Sellick et al, 2006). Molecular cytogenetic abnormalities associated with CLL have been reported (Stilgenbauer & Dohner, 2004), and include chromosome duplications (Juliusson et al, 1990;Molica et al, 1995;Dohner et al, 2000) and deletions, particularly 13q14 deletions (Juliusson et al, 1990;Dohner et al, 2000). Mouse models with known genetic backgrounds allow for the development of CLL murine models, which serve as valuable tools, not only in understanding disease mechanisms, but also in evaluating dietary/environmental triggers and efficacy of novel therapies. Mouse models of CLLThis article presents a comparison of several mouse models of CLL (Table I). With the exception of the New Zealand Black (NZB) model, all the models are induced by the expression of exogenous genes. The NZB mouse model of CLL, in contrast, is a de novo model that has been studied extensively as a model to investigate both autoimmune diseases, such as systemic lupus erythematosus (SLE), as well as B-cell lymphoproliferative disorders (Raveche et al, 1981;Manohar et al, 1982;Stall et al, 1988;Theofilopoulos, 1996). Autoreactivity has also been associated with CLL (Lugassy et al, 1992;Barcellini et al, 2006), and the NZB model displays mild autoimmunity that is associated with B-cell hyperactivity, resulting in autoimmune haemolytic anaemia ...

Reduced Thymic Aire Expression and Abnormal NF-κB2 Signaling in a Model of Systemic Autoimmunity

“…NZB mice develop a systemic autoimmune disease, including antierythrocyte, antinuclear, anti-single-stranded DNA, and antithymocyte autoantibodies. Pathogenesis is complex and polygenically controlled, with an array of immune abnormalities (15)(16)(17)(18)(19). Similarly to human systemic lupus erythematosus, disease onset occurs well into adulthood (mean onset, ϳ6 mo in mice; ϳ30 years in humans) (20,21).…”

Altering microRNA miR15a/16 Levels as Potential Therapy in CLL: Extrapolating from the De Novo NZB Mouse Model

“…We recently reported the presence of a mutation and a deletion in the 3' flanking region of miR15a/16-1 gene of NZB mouse model of CLL (See Fig.2A) (Raveche et al, 2007). This mutation in NZB is at a nearly identical location as a C to T point mutation found in CLL patients (Calin et al, 2005).…”

“…The disease penetrance is near 100% in these mice indicating the presence of a strong genetic bias. Similar to CLL patients, NZB mice exhibit age associated spontaneous development of CD5 + B220 dull IgM + B-1 cell malignancy [Reviewed by (Scaglione et al, 2007)]. These mice also exhibit an underlying autoimmunity characterized by the presence of anti-RBC and anti-DNA antibodies and hence are used as a model for Sytemic Lupus Erythematosus (SLE) [Reviewed by (Scaglione et al, 2007)].…”

“…Similar to CLL patients, NZB mice exhibit age associated spontaneous development of CD5 + B220 dull IgM + B-1 cell malignancy [Reviewed by (Scaglione et al, 2007)]. These mice also exhibit an underlying autoimmunity characterized by the presence of anti-RBC and anti-DNA antibodies and hence are used as a model for Sytemic Lupus Erythematosus (SLE) [Reviewed by (Scaglione et al, 2007)]. The underlying autoimmunity makes these mice an even more faithful model of human CLL since 10-25% of patients develop Autoimmune Hemolytic Anemia (AIHA) and 2% of patients develop autoimmune thrombocytopenia (Kipps and Carson, 1993).…”

“…In a Blood plenary paper, we reported the linkage of three loci -D14Mit160, D18Mit4, and D19Mit6 -to the presence of lymphoproliferative disease (LPD) in NZB mice (Raveche et al, 2007). Due to the homology to human Chr.13, we further analyzed the candidate genes in the D14Mit160 locus and discovered an association between miR15a/16-1 and CLL.…”