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CHRONIC LYMPHOCYTIC LEUKEMIA

CLL cell-derived exosomes alter the immune and hematopoietic systems

Leukemia volume 39, pages 1380–1394 (2025)Cite this article

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Abstract

The origins of immunosuppression, neutropenia, and anemia in patients with chronic lymphocytic leukemia (CLL) are not fully understood. Because in patients with CLL, circulating exosomes, which participate in cell-to-cell interactions, are CLL cell-derived, we examined whether those exosomes contribute to abnormal features of this disease. Our data revealed that CLL cell-derived exosomes engulfed by healthy donors’ monocytes, fibrocytes, and lymphocytes altered target-cell gene and protein expression and suppressed normal hematopoiesis. CLL cell-derived exosomes increased normal monocytes’ CD14 and CD16 expression such that it mimicked the accessory-cell profile and upregulated T cells’ checkpoint PD-1 and CD160 protein levels, potentially reducing T-cell-mediated anti-CLL activity. In normal B cells, CLL cell-derived exosomes induced apoptosis and CD5 expression, suggesting that CLL cell-derived exosomes eliminate B cells and not all CD19+/CD5+ cells in CLL patients are clonal. RNA sequencing and quantitative real-time PCR revealed that CLL cell-derived exosomes harbored RNAs of pro-apoptotic genes and genes that increase metabolism, induce proliferation, and induce constitutive PI3K-mTOR pathway activation. CLL cell-derived exosomes inhibited hematopoietic progenitor proliferation, hindering the supportive effect of monocyte-derived fibrocytes. Together, our findings suggest that CLL cell-derived exosomes disrupt the immune and hematopoietic systems and contribute to disease progression in patients with CLL.

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Fig. 1: Detection and characterization of plasma-derived exosomes.
Fig. 2: Production and release of exosomes by CLL cells.
Fig. 3: Transcriptional profile of CLL cell-derived exosomes.
Fig. 4: Impact of CLL cell-derived exosomes on monocyte cell-surface protein levels and gene expression profiles.
Fig. 5: Contribution of exosomes released by CLL cells to the dysregulation of normal fibrocytes and hematopoietic progenitors.
Fig. 6: Effects of CLL cell-derived exosomes on normal B cells.
Fig. 7: Alterations in normal T cells induced by CLL cell-derived exosomes.
Fig. 8: Apoptotic responses of CLL cells and normal lymphocytes to CLL cell-derived exosomes.

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Data availability

Original study data are available upon reasonable request to the corresponding authors for those wishing to reproduce or extend the research.

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Acknowledgements

This research was conducted in part at the core facilities of MD Anderson Cancer Center. Electron microscopy was performed at the High-Resolution Electron Microscopy Facility; RNA sequencing was performed at the Advanced Technology Genomics Core; tissue processing and staining were performed at the Research Histology Core Laboratory; and confocal microscopy, multispectral imaging, and mass cytometry analyses were performed at the Flow Cytometry and Cellular Imaging Core Facility. This work was supported by the CLL Global Research Foundation (CLLGRF to MTSB, GAC, and ZE). Additional support was provided by the National Cancer Institute, National Institutes of Health, through Cancer Center Support Grant P30 CA016672, which supports MD Anderson’s core facilities. We thank Stephanie Deming, Research Medical Library, MD Anderson Cancer Center, for editing the manuscript.

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Authors and Affiliations

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

    Ivo Veletic, David M. Harris, Uri Rozovski, Koichi Takahashi, Ping Li, Zhiming Liu, Taghi Manshouri, Ken Furudate, Muharrem Muftuoglu, William G. Wierda, Michael J. Keating & Zeev Estrov

  2. Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel

    Uri Rozovski

  3. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Maria Teresa S. Bertilaccio

  4. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    George A. Calin & Rares-Constantin Drula

  5. Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Anwar Hossain

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  1. Ivo Veletic
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Contributions

IV, UR, and ZE conceived the study. DMH, MTSB, PL, ZL, and RCD designed and performed experiments and collected data. IV, DMH, PL, RCD, and KF analyzed and interpreted the data. UR, MTSB, GAC, KT, WGW, and MJK validated the findings. DMH, TM, and ZE administered the project. MM and AH provided vital reagents and equipment. WGW, MJK, and ZE provided patients and clinical data. ZE acquired funding and supervised the study. IV prepared the figures. IV and ZE wrote the manuscript. All authors contributed to reviewing and editing the manuscript and gave final approval for publication.

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Correspondence to Ivo Veletic or Zeev Estrov.

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All procedures involving human participants were conducted in accordance with institutional guidelines, U.S. federal and state regulations, and the ethical standards laid down in the Declaration of Helsinki. Ethical approval was obtained from the Institutional Review Board of The University of Texas MD Anderson Cancer Center (IRB Registration Number: IRB00000121). Written informed consent was obtained from all participants for the use of anonymized data and biological specimens for research purposes.

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Veletic, I., Harris, D.M., Rozovski, U. et al. CLL cell-derived exosomes alter the immune and hematopoietic systems. Leukemia 39, 1380–1394 (2025). https://doi.org/10.1038/s41375-025-02590-x

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