Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Chronic lymphocytic leukemia

Rejection of adoptively transferred Eµ-TCL1 chronic lymphocytic leukemia cells in C57BL/6 substrains or knockout mouse lines

Leukemia volume 33, pages 1514–1539 (2019)Cite this article

Subjects

To the Editor:

The Eμ-TCL1 mouse model [1] is widely used to study pathological mechanisms of chronic lymphocytic leukemia (CLL) and its microenvironment. Eμ-TCL1 mice develop a CLL-like disease at 8 to 12 months of age [1], and studies in this mouse model have extensively improved our knowledge on microenvironmental regulation of CLL [2, 3]. Tumor cells from Eμ-TCL1 mice can be isolated from the spleen and adoptively transferred into young syngeneic mice, which as a result develop leukemia typically in around 4–6 weeks [4]. To identify the drivers of disease in the microenvironment of CLL, several groups used this adoptive transfer approach with knockout mice as recipients, and thereby studied CLL development in a microenvironment that is deficient for molecules of interest [2, 5,6,7,8]. When we tested CLL development after adoptive transfer of Eµ-TCL1 tumor cells in several knockout mouse models, we repeatedly observed lack of tumor growth in these mice. Our further analyses indicated that leukemia development in transplanted mice is highly sensitive to slight differences in the genetic background of donor and recipient mice, including differences in the expression of knockout genes. Therefore, we hypothesized that alloantigens, as a consequence of genetic differences, lead to graft rejection in the Eµ-TCL1 adoptive transfer model.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

References

  1. Bichi R, Shinton SA, Martin ES, Koval A, Calin GA, Cesari R, et al. Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proc Natl Acad Sci USA. 2002;99:6955–60.

    Article  CAS  Google Scholar 

  2. Hanna BS, McClanahan F, Yazdanparast H, Zaborsky N, Kalter V, Rossner PM, et al. Depletion of CLL-associated patrolling monocytes and macrophages controls disease development and repairs immune dysfunction in vivo. Leukemia. 2016;30:570–9.

    Article  CAS  Google Scholar 

  3. McClanahan F, Hanna B, Miller S, Clear AJ, Lichter P, Gribben JG, et al. PD-L1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia. Blood. 2015;126:203–11.

    Article  CAS  Google Scholar 

  4. Zanesi N, Aqeilan R, Drusco A, Kaou M, Sevignani C, Costinean S, et al. Effect of Rapamycin on Mouse Chronic Lymphocytic Leukemia and the Development of Nonhematopoietic Malignancies in Eμ-TCL1 Transgenic Mice. Cancer Res. 2006;66:915–20.

    Article  CAS  Google Scholar 

  5. Lutzny G, Kocher T, Schmidt-Supprian M, Rudelius M, Klein-Hitpass L, Finch AJ, et al. Protein kinase c-beta-dependent activation of NF-kappaB in stromal cells is indispensable for the survival of chronic lymphocytic leukemia B cells in vivo. Cancer Cell. 2013;23:77–92.

    Article  CAS  Google Scholar 

  6. Nguyen PH, Fedorchenko O, Rosen N, Koch M, Barthel R, Winarski T, et al. LYN Kinase in the Tumor Microenvironment Is Essential for the Progression of Chronic Lymphocytic Leukemia. Cancer Cell. 2016;30:610–22.

    Article  CAS  Google Scholar 

  7. Alhakeem SS, McKenna MK, Oben KZ, Noothi SK, Rivas JR, Hildebrandt GC, et al. Chronic Lymphocytic Leukemia–Derived IL-10 Suppresses Antitumor Immunity. The Journal of Immunology. 2018;200:4180–9.

    Article  CAS  Google Scholar 

  8. Dong S, Harrington BK, Hu EY, Greene JT, Lehman AM, Tran M, et al. PI3K p110δ inactivation antagonizes chronic lymphocytic leukemia and reverses T cell immune suppression. J Clin Invest. 2018;129.

  9. Hanna BS, Roessner PM, Yazdanparast H, Colomer D, Campo E, Kugler S, et al. Control of chronic lymphocytic leukemia development by clonally-expanded CD8+ T-cells that undergo functional exhaustion in secondary lymphoid tissues. Leukemia. 2018 https://doi.org/10.1038/s41375-018-0250-6. [Epub ahead of print].

  10. Mekada K, Abe K, Murakami A, Nakamura S, Nakata H, Moriwaki K, et al. Genetic differences among C57BL/6 substrains. Exp Anim. 2009;58:141–9.

    Article  CAS  Google Scholar 

  11. Bourdi M, Davies JS, Pohl LR. Mispairing C57BL/6 substrains of genetically engineered mice and wild-type controls can lead to confounding results as it did in studies of JNK2 in acetaminophen and concanavalin A liver injury. Chem Res Toxicol. 2011;24:794–6.

    Article  CAS  Google Scholar 

  12. Heng TS, Painter MW. Immunological Genome Project C. The Immunological Genome Project: networks of gene expression in immune cells. Nat Immunol. 2008;9:1091–4.

    Article  CAS  Google Scholar 

  13. Göbel M, Eisele L, Möllmann M, Hüttmann A, Johansson P, Scholtysik R, et al. Progranulin Is a Novel Independent Predictor of Disease Progression and Overall Survival in Chronic Lymphocytic Leukemia. PLoS ONE. 2013;8:e72107.

    Article  CAS  Google Scholar 

  14. Onoe K, Gotohda T, Nishihori H, Aranami T, Iwabuchi C, Iclozan C, et al. Positive and negative selection of T cell repertoires during differentiation in allogeneic bone marrow chimeras. Transpl Immunol. 2003;12:79–88.

    Article  CAS  Google Scholar 

  15. Holl EK. Generation of bone marrow and fetal liver chimeric mice. Methods Mol Biol. 2013;1032:315–21.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the German José Carreras Foundation (R14/23), and the German Cancer Aid (grant number 112069), by the BMBF-Network “PReCiSe” (031L0076A) and the ERA-NET TRANSCAN-2 program JTC 2014–project FIRE-CLL.

Author contributions

SÖ and PMR designed the study, performed experiments, analyzed and interpreted data, prepared figures, and wrote the manuscript. LS-E, HY and BSH designed and performed experiments, analyzed and interpreted data, and prepared figures. VK performed experiments. PL supervised the study and reviewed the manuscript. MS designed and supervised the study, interpreted data, and wrote the manuscript.

Author information

Author notes

  1. These authors contributed equally: Selcen Öztürk, Philipp M. Roessner

Authors and Affiliations

  1. Department of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Selcen Öztürk, Philipp M. Roessner, Lena Schulze-Edinghausen, Haniyeh Yazdanparast, Verena Kalter, Peter Lichter, Bola S. Hanna & Martina Seiffert

Authors
  1. Selcen Öztürk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philipp M. Roessner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lena Schulze-Edinghausen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haniyeh Yazdanparast
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Verena Kalter
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peter Lichter
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bola S. Hanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Martina Seiffert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martina Seiffert.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Öztürk, S., Roessner, P.M., Schulze-Edinghausen, L. et al. Rejection of adoptively transferred Eµ-TCL1 chronic lymphocytic leukemia cells in C57BL/6 substrains or knockout mouse lines. Leukemia 33, 1514–1539 (2019). https://doi.org/10.1038/s41375-018-0332-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-018-0332-5

This article is cited by

Search

Advanced search

Quick links