Meta-Analysis Reveals Significant Sex Differences in Chronic Lymphocytic Leukemia Progression in the Eµ-TCL1 Transgenic Mouse Model

Koch, Maximilian; Reinartz, Sebastian; Saggau, Julia; Knittel, Gero; Rosen, Natascha; Fedorchenko, Oleg; Thelen, Lisa; Barthel, Romy; Reinart, Nina; Seeger-Nukpezah, Tamina; Reinhardt, Hans Christian; Hallek, Michael; Nguyen, Phuong-Hien

doi:10.3390/cancers12071980

Cited by 8 publications

(6 citation statements)

References 41 publications

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“…2c). These nding are in contrast to prior reports which suggested that male mice had a survival advantage in the Eµ-TCL1 model [20]. However, prolonged survival of female recipients was also observed in the Eµ-Myc model, another syngeneic model of B cell malignancy (Figure S2).…”

Section: Sex Differences In Primary Engraftmentcontrasting

confidence: 96%

“…In particular, studies aimed at understanding the immune microenvironment often necessitate the use of immunocompetent murine models such as the Eμ-TCL1 model [19]. Given prior reports of sex differences in the Eμ-TCL1 model [20] and the preponderance of evidence suggesting sex differences are evident in other syngeneic models [21][22][23][24] we sought to perform a prospective analysis of the effect of sex and aging on the Eμ-TCL1 adoptive transfer model.…”

Section: Introductionmentioning

confidence: 99%

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

Sharpe

Perry

Hertlein

et al. 2022

Blood

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Background:The Eμ-TCL1 syngeneic model is the most widely used mouse model of chronic lymphocytic leukemia and has been extensively used to understand the pathogenesis of select genes, the 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 not only the development of cancers but also the e cacy and toxicity of speci c cancer therapies. However, despite the predominance of older males in CLL patient demographics, the Eμ-TCL1 adoptive transfer studies have used almost exclusively young female recipient mice.Methods:In this study we performed primary and secondary adoptive transfer experiments in order to understand the impact of recipient age and sex on the development of disease as assessed by ow cytometry and survival in the Eμ-TCL1 adaptive transfer model.Results:We found that young female recipients had pro-longed survival in a primary adoptive transfer, however sex differences were not observed in a subsequent secondary adoptive transfer experiment. Furthermore, while recipient age did not have a signi cant effect on the rate of disease establishment or survival in female mice, aged male mice had a signi cantly decreased rate of Eμ-TCL1 tumor engraftment.Conclusions:These ndings suggest that age and sex differences must be considered in the experimental design of studies using the Eμ-TCL1 adaptive transfer model of CLL.

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Section: Sex Differences In Primary Engraftmentcontrasting

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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

Sharpe

Perry

Hertlein

et al. 2022

Blood

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“…It should be emphasized that the observed increase in median survival of CD73deficient versus CD73-proficient Eµ-TCL1 tg/wt male mice (i.e., nearly 3 months) is in the same range as what has been reported for ibrutinib treatment in this model [33]. CD73 deficiency did not simply exacerbate a preexisting survival sex bias in the Eµ-TCL transgenic mouse model, as reported by Koch et al [34]. We did not observe such bias in our studies.…”

Section: Discussionsupporting

confidence: 84%

“…CD73 biology may differ between mice and humans as CD73 −/− mice do not fully recapitulate CD73 deficiency in humans [35,36]. In addition, since disease severity is greater in men with CLL [2], but slightly milder in male Eµ-TCL1 transgenic mice [34], aspects of CLL pathogenesis may not be fully recapitulated by the mouse model used in this report.…”

Section: Discussionmentioning

confidence: 93%

CD73 Promotes Chronic Lymphocytic Leukemia

Allard

Chrobák

Barèche

et al. 2022

Cancers

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The ecto-nucleotidase CD73 is an important immune checkpoint in tumor immunity that cooperates with CD39 to hydrolyze pro-inflammatory extracellular ATP into immunosuppressive adenosine. While the role of CD73 in immune evasion of solid cancers is well established, its role in leukemia remains unclear. To investigate the role of CD73 in the pathogenesis of chronic lymphocytic leukemia (CLL), Eµ-TCL1 transgenic mice that spontaneously develop CLL were crossed with CD73−/− mice. Disease progression in peripheral blood and spleen, and CLL markers were evaluated by flow cytometry and survival was compared to CD73-proficient Eµ-TCL1 transgenic mice. We observed that CD73 deficiency significantly delayed CLL progression and prolonged survival in Eµ-TCL1 transgenic mice, and was associated with increased accumulation of IFN-γ+ T cells and effector-memory CD8+ T cells. Neutralizing IFN-γ abrogated the survival advantage of CD73-deficient Eµ-TCL1 mice. Intriguingly, the beneficial effects of CD73 deletion were restricted to male mice. In females, CD73 deficiency was uniquely associated with the upregulation of CD39 in normal lymphocytes and sustained high PD-L1 expression on CLL cells. In vitro studies revealed that adenosine signaling via the A2a receptor enhanced PD-L1 expression on Eµ-TCL1-derived CLL cells, and a genomic analysis of human CLL samples found that PD-L1 correlated with adenosine signaling. Our study, thus, identified CD73 as a pro-leukemic immune checkpoint in CLL and uncovered a previously unknown sex bias for the CD73-adenosine pathway.

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“…Finally, this Special Issue includes a brief report by Koch and colleagues that summarizes the results from a meta-analysis on a large cohort of TCL1 mice, showing that leukemia progression is significantly accelerated in female TCL1 mice compared to males and that additional genetic lesions, besides the TCL1 transgene, further contribute to disease progression [34]. These findings pose several questions on the use of this model, the only one, up to now, available to mimic the human disease apart from xenografts.…”

mentioning

confidence: 99%