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Chronic Lymphocytic Leukemia

Stromal cells modulate TCL1 expression, interacting AP-1 components and TCL1-targeting micro-RNAs in chronic lymphocytic leukemia

Leukemia volume 26, pages 1812–1820 (2012)Cite this article

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Abstract

The tissue microenvironment in chronic lymphocytic leukemia (CLL) has an increasingly recognized role in disease progression, but the molecular mechanisms of cross talk between CLL cells and their microenvironment remain incompletely defined. Bone marrow stromal cells (BMSC) protect CLL cells from apoptosis in a contact-dependent fashion, and have been used for the identification of key pathways such as the CXCR4–CXCL12 axis. To further dissect the molecular impact of BMSC on survival and the molecular activation signature of CLL cells, we co-cultured CLL cells with different BMSC. Gene expression profiling of CLL cells revealed that the lymphoid proto-oncogene TCL1 was among the top genes upregulated in CLL cells by BMSC. TCL1 mRNA and protein upregulation by BMSC was paralleled by decreases of TCL1-interacting FOS/JUN, and confirmed by qRT-PCR, immunoblotting, immunoprecipitations, and flow cytometry. Stroma mediated increases in TCL1 were also associated with decreased levels of TCL1-regulatory micro-RNAs (miR-29b, miR-181b, miR-34b). These findings demonstrate that the microenvironment has a proactive role in the regulation of the known signaling enhancer and pro-survival molecule TCL1 in CLL. This provides a further rationale for therapeutically targeting the cross talk between CLL and BMSC.

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Acknowledgements

This study was supported by grants from the CLL Global Research Foundation (to WW, AR, MH and JAB) a Cancer Prevention and Research Institute of Texas (CPRIT) grant (to JAB), a DFG young investigator award (HE3553/2-1, to MH), a Max-Eder Award by the Deutsche Krebshilfe (to MH) and the CECAD Initiative of Cologne University (to JMB and MH).

Author Contributions

MS, EV and AB performed CLL-BMSC co-cultures, RNA extraction, flow cytometry, immunoblots and immunoprecipitations, data analysis, and designed the figures and tables. EH performed the microarray studies and -analysis and qRT-PCR. JMB performed the qRT-PCR, immunoblotting and miR expression analysis. MJK and WGW provided CLL samples and reviewed data and the manuscript. AR designed the microarray studies and -analysis with JAB, and reviewed data and the manuscript. MH designed confirmatory experiments and reviewed data. JAB designed the research, supervised the study, analyzed the data and wrote the paper with MS, EH, JMB, AR and MH.

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Author notes

  1. M Sivina, E Hartmann, E Vasyutina and J M Boucas: These authors contributed equally to this work.

  2. M Herling and J A Burger: Co-corresponding authors.

Authors and Affiliations

  1. Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M Sivina, M J Keating, W G Wierda & J A Burger

  2. Institute of Pathology, University of Würzburg, Würzburg, Germany

    E Hartmann & A Rosenwald

  3. Department of Medicine 1, University of Cologne, Cologne, Germany

    E Vasyutina, J M Boucas, A Breuer & M Herling

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  1. M Sivina
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Correspondence to M Herling or J A Burger.

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Sivina, M., Hartmann, E., Vasyutina, E. et al. Stromal cells modulate TCL1 expression, interacting AP-1 components and TCL1-targeting micro-RNAs in chronic lymphocytic leukemia. Leukemia 26, 1812–1820 (2012). https://doi.org/10.1038/leu.2012.63

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