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Molecular Targets for Therapy

Disruption of HOX activity leads to cell death that can be enhanced by the interference of iron uptake in malignant B cells

Leukemia volume 24, pages 1555–1565 (2010)Cite this article

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Abstract

The HOX genes encode a family of transcription factors that are dysregulated in several malignancies and have been implicated in oncogenesis and cancer cell survival. Disruption of HOX protein function using the peptide HXR9 has shown anti-tumor effects against melanoma, lung cancer and renal cancer. In this report, we evaluated the expression of all 39 HOX genes in a panel of six malignant B-cell lines, including multiple myeloma cells and found different levels of expression of HOX family members suggesting that they also have a role in malignant B-cell survival. We show that disrupting HOX function using the peptide HXR9 induces significant cytotoxicity in the entire panel of cell lines. Importantly, we found that the cytotoxic effects of HXR9 can be enhanced by combining it with ch128.1Av, an antibody-avidin fusion protein specific for the human transferrin receptor 1 (CD71). Iron starvation induced by the fusion protein contributes to the enhanced effect and involves, at least in part, the induction of a caspase-independent pathway. These results show the relevance of HOX proteins in malignant B-cell survival and suggest that our therapeutic strategy may be effective in the treatment of incurable B-cell malignancies such as multiple myeloma.

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Acknowledgements

We thank Dr Lawrence Boise (Emory University, Atlanta, GA, USA) for providing the KMS-11 cell line and Drs Kenneth Anderson and Darminder Chauhan (Dana-Farber Cancer Institute, Boston, MA). for providing the MM.1S cell line. This work was supported in part by NIH/NCI Grants R01CA107023, K01CA138559, R01 supplement CA57152-13S1 and the training grant T32-CA009120. Our work was also supported by the Howard Hughes Medical Institute Gilliam Fellowship, the Whitcome Fellowship of the Molecular Biology Interdepartmental Ph.D. Program at UCLA, The Prostate Project (UK), and Cancer Research UK (C7822/A3832). The UCLA Jonsson Comprehensive Cancer Center and Center for AIDS Research Flow Cytometry Core Facility is supported by the NIH Awards CA-16042 and AI-28697, the Jonsson Cancer Center, the UCLA AIDS Institute, and the UCLA School of Medicine.

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Authors and Affiliations

  1. Division of Surgical Oncology, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    T R Daniels, I I Neacato, J A Rodríguez & M L Penichet

  2. The Molecular Biology Institute, University of California, Los Angeles, CA, USA

    J A Rodríguez & M L Penichet

  3. Faculty of Health and Medical Sciences, Postgraduate Medical School, University of Surrey, Guildford, UK

    H S Pandha & R Morgan

  4. Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    M L Penichet

  5. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA

    M L Penichet

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Correspondence to M L Penichet.

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Daniels, T., Neacato, I., Rodríguez, J. et al. Disruption of HOX activity leads to cell death that can be enhanced by the interference of iron uptake in malignant B cells. Leukemia 24, 1555–1565 (2010). https://doi.org/10.1038/leu.2010.142

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