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

Richter’s syndrome (RS) is an aggressive B-cell lymphoma arising from chroniclymphocytic leukemia (CLL). RS patients are generally unresponsive both toconventional and B-cell receptor-targeted agents such as ibrutinib. Mouse models thatmimic the biology and therapeutic response of RS are lacking, which hampers thedevelopment of alternative treatment strategies urgently needed to improve the dismaloutcome of RS patients. Aberrant Myc expression is a major factor of RSpathogenesis. To investigate Myc overexpression in the context of CLL, we generatedEμ-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 asignificantly reduced lifespan. Injection of cells from diseased Eμ-TCL1xMyc into WTmice established a disease similar to that in double-transgenic mice. Both Eμ-TCL1xMyc mice and mice with disease after adoptive transfer failed to respond toibrutinib. Effective and durable disease control was however observed by selectiveinhibition of nuclear export protein exportin-1 (XPO1) using a compound currently inclinical 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, mimickingclinical behavior and therapeutic responses seen in RS patients.