Eµ-TCL1xMyc Mice as a Therapeutic Model of Accelerated B-cell Malignancy

Richter's syndrome (RS) is an aggressive B-cell lymphoma arising from chronic lymphocytic leukemia (CLL). RS patients are generally unresponsive both to conventional and B-cell receptor-targeted agents such as ibrutinib. Mouse models that mimic the biology and therapeutic response of RS are lacking, which hampers the development of alternative treatment strategies urgently needed to improve the dismal outcome of RS patients. Aberrant Myc expression is a major factor of RS pathogenesis. To investigate Myc overexpression in the context of CLL, we generated Eµ-TCL1 mice with B-cell restricted Myc expression. Eµ-TCL1xMyc mice uniformly developed highly aggressive lymphoid disease with histologically and immunophenotypically distinct concomitant CLL and B-cell lymphoma, leading to a significantly reduced lifespan. Injection of cells from diseased Eµ-TCL1xMyc into WT mice established a disease similar to that in double-transgenic mice. Both Eµ-TCL1xMyc mice and mice with disease after adoptive transfer failed to respond to ibrutinib. Effective and durable disease control was however observed by selective inhibition of nuclear export protein exportin-1 (XPO1) using a compound currently in clinical development for relapsed/refractory malignancies, including CLL and lymphoma. Altogether, the Eµ-TCL1xMyc mouse model represents a new preclinical tool for experimental drug testing of aggressive lymphoma in the context of CLL, mimicking clinical behavior and therapeutic responses seen in RS patients. Overall design: Eµ-TCL1 transgenic mice developing CLL and Eµ-Myc transgenic mice developing B-cell lymphoma have previously been described (Bichi et al, 2002, Adams et al, 1985). c-Myc and wild type (WT) mice were purchased from Jackson laboratories (Bar Harbor, ME). C57BL/6J females were crossed with Eµ-Myc hemizygous males to produce Eµ-Myc hemizygous or non-transgenic (ntg) pups. Eµ-TCL1-B6 homozygous females were crossed with Eµ-Myc hemizygous males to produce Eµ-TCL1B6 hemizygous/Eµ-Myc hemizygous (abbreviated to Eµ-TCL1xMyc or double transgenic (dTG)) or Eµ-TCL1B6 hemizygous/ntg pups. Survival of transgenic mice was assessed in all transgenic colony mice born within a 24 month period. Histopathological and immunophenotype assessments were conducted in spleen, lymph node, bone, and blood to characterize malignancy.