Eμ-TCL1xMyc: A Novel Mouse Model for Concurrent CLL and B-Cell Lymphoma

Lucas, Fabienne; Rogers, Kerry A.; Harrington, Bonnie K.; Pan, Alexander; Yu, Lianbo; Breitbach, Justin; Bundschuh, Ralf; Goettl, Virginia M.; Hing, Zachary A.; Kanga, Parviz; Mantel, Rose; Sampath, Deepa; Smith, Lisa L.; Wasmuth, Ronni; White, Danielle K.; Yan, Pearlly S.; Byrd, John C.; Lapalombella, Rosa

doi:10.1158/1078-0432.ccr-19-0273

Cited by 21 publications

(19 citation statements)

References 48 publications

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“…Altogether, males ( n = 160) had a median OS of 397 days, whereas the median OS of females ( n = 158) was only 360 days, implying a significantly longer OS of 37 days in males than females ( Figure 2 A). Recently, the Eµ-TCL1 transgenic mice have been crossed with other mouse lines lacking tumor-suppressor genes [ 15 ] or harboring an additional oncogene [ 16 ], leading to accelerated leukemia development and enhanced disease aggressiveness in these mice. To investigate whether these additional transgenic alleles could compromise the male–female bias in the Eµ-TCL1 transgenic mice, we analyzed the OS of Eµ-TCL1 tg/wt ; CD19Cre Cre/wt ; Trp53 fl/fl (TCP) mice—a mouse model with features of high-risk human CLL.…”

Section: Resultsmentioning

confidence: 99%

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

Koch

Reinartz

Saggau

et al. 2020

Cancers

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The Eµ-TCL1 transgenic mouse model represents the most widely and extensively used animal model for chronic lymphocytic leukemia (CLL). In this report, we performed a meta-analysis of leukemia progression in over 300 individual Eµ-TCL1 transgenic mice and discovered a significantly accelerated disease progression in females compared to males. This difference is also reflected in an aggressive CLL mouse model with additional deletion of Tp53 besides the TCL1 transgene. Moreover, after serial adoptive transplantation of murine CLL cells, female recipients also succumbed to CLL earlier than male recipients. This sex-related disparity in the murine models is markedly contradictory to the human CLL condition. Thus, due to our observation we urge both careful consideration in the experimental design and accurate description of the Eµ-TCL1 transgenic cohorts in future studies.

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Section: Resultsmentioning

confidence: 99%

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

Koch

Reinartz

Saggau

et al. 2020

Cancers

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“…T and B cells were enriched using EasySep kit (Stem Cell Technologies, Vancouver, BC, Canada). Flow optimizations and protocols were used as previously described [61]. Gating strategy and graphs from representative C57BL/6 and Eµ-TCL1 whole blood are shown in the supplementary materials.…”

Section: Flow Cytometrymentioning

confidence: 99%

“…Organs were harvested from colony mice at indicated ages or upon meeting euthanasia criteria. Tissues were fixed, processed and stained with hematoxylin and eosin (H&E) (Leica) as previously described [61]. Photographs were taken using an Olympus SC30 camera with an Olympus BX53 microscope.…”

Section: Histopathologymentioning

confidence: 99%

Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia

et al. 2021

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Background Exportin 1 (XPO1/CRM1) is a key mediator of nuclear export with relevance to multiple cancers, including chronic lymphocytic leukemia (CLL). Whole exome sequencing has identified hot-spot somatic XPO1 point mutations which we found to disrupt highly conserved biophysical interactions in the NES-binding groove, conferring novel cargo-binding abilities and forcing cellular mis-localization of critical regulators. However, the pathogenic role played by change-in-function XPO1 mutations in CLL is not fully understood. Methods We performed a large, multi-center retrospective analysis of CLL cases (N = 1286) to correlate nonsynonymous mutations in XPO1 (predominantly E571K or E571G; n = 72) with genetic and epigenetic features contributing to the overall outcomes in these patients. We then established a mouse model with over-expression of wildtype (wt) or mutant (E571K or E571G) XPO1 restricted to the B cell compartment (Eµ-XPO1). Eµ-XPO1 mice were then crossed with the Eµ-TCL1 CLL mouse model. Lastly, we determined crystal structures of XPO1 (wt or E571K) bound to several selective inhibitors of nuclear export (SINE) molecules (KPT-185, KPT-330/Selinexor, and KPT-8602/Eltanexor). Results We report that nonsynonymous mutations in XPO1 associate with high risk genetic and epigenetic features and accelerated CLL progression. Using the newly-generated Eµ-XPO1 mouse model, we found that constitutive B-cell over-expression of wt or mutant XPO1 could affect development of a CLL-like disease in aged mice. Furthermore, concurrent B-cell expression of XPO1 with E571K or E571G mutations and TCL1 accelerated the rate of leukemogenesis relative to that of Eµ-TCL1 mice. Lastly, crystal structures of E571 or E571K-XPO1 bound to SINEs, including Selinexor, are highly similar, suggesting that the activity of this class of compounds will not be affected by XPO1 mutations at E571 in patients with CLL. Conclusions These findings indicate that mutations in XPO1 at E571 can drive leukemogenesis by priming the pre-neoplastic lymphocytes for acquisition of additional genetic and epigenetic abnormalities that collectively result in neoplastic transformation.

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“…30 In a recent study, researchers generated a double-transgenic mouse model (Em-TCL1xMyc) to study therapeutic strategies in concurrent CLL and B-cell lymphoma. 31 However, the Em-TCL1 model typically requires 6 months for the appearance of circulating tumor cells. 29 In contrast, xenotransplantation of MEC-1 cells provides a more immediate preclinical tool.…”

Section: Discussionmentioning

confidence: 99%

Development and characterization of prototypes for in vitro and in vivo mouse models of ibrutinib-resistant CLL

Aslan¹,

Kısmalı²,

Chen³

et al. 2021

Blood Advances

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Although ibrutinib improves the overall survival of patients with chronic lymphocytic leukemia (CLL), some patients still develop resistance, most commonly through point mutations affecting cysteine residue 481 (C481) in Bruton’s tyrosine kinase (BTKC481S and BTKC481R). To enhance our understanding of the biological impact of these mutations, we established cell lines that overexpress wild-type or mutant BTK in in vitro and in vivo models that mimic ibrutinib-sensitive and -resistant CLL. MEC-1 cell lines stably overexpressing wild-type or mutant BTK were generated. All cell lines coexpressed GFP, were CD19+ and CD23+, and overexpressed BTK. Overexpression of wild-type or mutant BTK resulted in increased signaling, as evidenced by the induction of p-BTK, p-PLCγ2, and p-extracellular signal–related kinase (ERK) levels, the latter further augmented upon IgM stimulation. In all cell lines, cell cycle profiles and levels of BTK expression were similar, but the RNA sequencing and reverse-phase protein array results revealed that the molecular transcript and protein profiles were distinct. To mimic aggressive CLL, we created xenograft mouse models by transplanting the generated cell lines into Rag2−/−γc−/− mice. Spleens, livers, bone marrow, and peripheral blood were collected. All mice developed CLL-like disease with systemic involvement (engraftment efficiency, 100%). We observed splenomegaly, accumulation of leukemic cells in the spleen and liver, and macroscopically evident necrosis. CD19+ cells accumulated in the spleen, bone marrow, and peripheral blood. The overall survival duration was slightly lower in mice expressing mutant BTK. Our cell lines and murine models mimicking ibrutinib-resistant CLL will serve as powerful tools to test reversible BTK inhibitors and novel, non–BTK-targeted therapeutics.

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Eμ-TCL1xMyc: A Novel Mouse Model for Concurrent CLL and B-Cell Lymphoma

Cited by 21 publications

References 48 publications

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

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

Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia

Development and characterization of prototypes for in vitro and in vivo mouse models of ibrutinib-resistant CLL

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