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Tetraspanin CD82 regulates bone marrow homing of acute myeloid leukemia by modulating the molecular organization of N-cadherin

Oncogene volume 35, pages 4132–4140 (2016)Cite this article

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Abstract

Communication between acute myeloid leukemia (AML) and the bone marrow microenvironment is known to control disease progression. Therefore, regulation of AML cell trafficking and adhesion to the bone marrow is of significant interest. In this study, we demonstrate that differential expression of the membrane scaffold CD82 modulates the bone marrow homing of AML cells. By combining mutational analysis and super-resolution imaging, we identify membrane protein clustering by CD82 as a regulator of AML cell adhesion and bone marrow homing. Cluster analysis of super-resolution data indicates that N-linked glycosylation and palmitoylation of CD82 are both critical modifications that control the microdomain organization of CD82 as well as the nanoscale clustering of associated adhesion protein, N-cadherin. We demonstrate that the inhibition of CD82 glycosylation increases the molecular packing of N-cadherin and promotes the bone marrow homing of AML cells. In contrast, we find that the inhibition of CD82 palmitoylation disrupts the formation and organization of N-cadherin clusters and significantly diminishes bone marrow trafficking of AML. Taken together, these data establish a mechanism where the membrane organization of CD82, through specific posttranslational modifications, regulates N-cadherin clustering and membrane density, which impacts the in vivo trafficking of AML cells. As such, these observations provide an alternative model for targeting AML where modulation of protein organization within the membrane may be an effective treatment therapy to disrupt the bone marrow homing potential of AML cells.

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Acknowledgements

We would like to acknowledge all of the funding sources that made this work possible. This includes funding from an NIH R01 HL122483-01A1 to JMG, a New Mexico INBRE grant subaward to JMG (NIH P20 GM103451), pilot funding from the University of New Mexico Cancer Center (NIH P30CA118100), an American Cancer Society Institutional Research Grant, a Post-Doctoral Training Fellowship to KDM (NIH T32 HL007736), Graduate Student Training Fellowships to CMT from the NM Spatiotemporal Modeling Center (NIH P50 GM085273) and (NIH F31 HL124977), and a Graduate Student Training Fellowship to CSR (NIH T32 HL007736). We also thank the NM Spatiotemporal Modeling Center for supporting the Super-Resolution Imaging Core Facility (NIH P50 GM085273) and the University of New Mexico Cancer Center (NIH P30CA118100) for use of the Keck-UNM Small Animal Models and Imaging Shared Resource. This work was also supported through faculty start-up funds to JMG from the University of New Mexico Department of Pathology. Finally, we would like to acknowledge the technical assistance of Rebecca J. Dodd and Dr I-Ming Chen, University of New Mexico Health Sciences Center. In addition, we would like to acknowledge the assistance of Dr Ravi Majeti, Division of Hematology, Institute for Stem Cell Biology and Regenerative Medicine, and Cancer Institute, Stanford University and the Stanford University Division of Hematology Tissue Bank for samples. (http://www.nature.com/onc)

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  1. K D Marjon and C M Termini: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM, USA

    K D Marjon, C M Termini, K L Karlen, C Saito-Reis, C E Soria & J M Gillette

  2. Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM, USA

    K A Lidke

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  1. K D Marjon
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Correspondence to J M Gillette.

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Marjon, K., Termini, C., Karlen, K. et al. Tetraspanin CD82 regulates bone marrow homing of acute myeloid leukemia by modulating the molecular organization of N-cadherin. Oncogene 35, 4132–4140 (2016). https://doi.org/10.1038/onc.2015.449

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