Age and Sex Differences in the Eμ-TCL1 Adoptive Transfer Mouse Model of CLL

The Eμ-TCL1 model is the most widely used syngeneic mouse model of chronic lymphocytic leukemia (CLL) and has been extensively used to understand the pathogenesis of select genes, effect of the immune microenvironment and for pre-clinical drug development studies. Recently there has been an increasing awareness of the impact of age and sex differences on the development of cancers along with the efficacy and toxicity of specific cancer therapies. However, despite the predominance of older males in CLL patient demographics, Eμ-TCL1 adoptive transfer (AT) studies have used almost exclusively young female mice. We therefore sought to understand how recipient age and sex impact the development and survival of the Eμ-TCL1 model in order to allow for age and sex diverse pre-clinical studies using this model.

First, a primary AT mouse experiment was performed to assess the impact of recipient sex on engraftment and survival. We found that in primary AT, sex matched recipients had faster engraftment and higher leukemia burden in the peripheral blood at 1- and 3-months post-AT. However, while disease burden was correlated with survival, young female recipients had prolonged survival compared to young male mice regardless of donor sex. Notably, sex differences were more prominent in recipients with relatively indolent disease with a median survival of median survival 178 and 132 days respectively as compared with more aggressive donors where sex differences were not apparent and both male and female recipients had a median survival of 87 days. A subsequent secondary AT using splenocytes isolated from primary AT recipients showed a more aggressive disease course (median survival 56 days) in which sex differences were not present. Additional secondary transfer experiments were performed to determine the impact of recipient age. Three age cohorts of male and female recipient mice (young 3-6 months) middle aged (9-12 months) and old (18-22 months) received a secondary AT. These ages were selected to correspond to approximate human ages of 20-30 years, 40-45 years, and 56 to 65 years old. While recipient age did not have a significant effect on the rate of disease establishment or survival in female mice, old male mice had a significantly decreased rate of Eμ-TCL1 tumor engraftment, and higher rates of failure to engraft, but similar overall survival to younger cohorts.

In conclusion, we show that age and sex differences are present in the Eμ-TCL1 model, with female mice having prolonged survival compared to male mice particularly in indolent disease presentations. These findings suggest that age and sex differences must be considered in the experimental design using the Eμ-TCL1 adaptive transfer model of CLL.

Byrd:Xencor, Inc: Research Funding; AstraZeneca: Consultancy; Syndax: Consultancy; Pharmacyclics LLC: Honoraria, Research Funding; Kura Oncology, Inc: Consultancy; Novartis: Consultancy, Honoraria; Vincerx Pharma: Current equity holder in publicly-traded company; TG Therapeutics: Honoraria; Janssen Pharmaceuticals, Inc.: Consultancy.