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

Summary Mouse 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.