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Induction of iron excess restricts malignant plasma cells expansion and potentiates bortezomib effect in models of multiple myeloma

Leukemia volume 31, pages 967–970 (2017)Cite this article

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Iron is a fundamental nutrient and cancer cells may benefit from increased iron availability for proliferation. However, excess iron is toxic as it catalyzes reactive oxygen species (ROS) formation.1 Cells react to excess iron by increasing the iron storage protein ferritin, by reducing the iron importer transferrin receptor 1 (TfR1 or CD71) and by increasing the expression of the iron exporter ferroportin through the function of iron regulatory proteins.2 At the systemic level, excess iron stimulates the expression of the liver hormone hepcidin, which promotes degradation of ferroportin, reducing both dietary iron absorption from duodenal enterocytes and iron release from liver and macrophage stores.2 Plasma cells (PCs) are potentially highly sensitive to excess iron because they have high levels of hydrogen peroxide, a by-product of antibody synthesis, which may generate ROS through Fenton reaction.3, 4 We have observed that normal murine PCs, to maintain low intracellular iron, express low TfR1 and high ferroportin.5 Multiple myeloma (MM) PCs must balance the need to increase iron uptake for proliferation with that of avoiding iron toxicity. Indeed, they have high TfR1 (Bordini et al.5 and Gu et al.6 and personal observations), an event favored by MYC overexpression7 that frequently occurs in MM patients,8 but concurrently maintain high ferroportin levels to guarantee export of iron excess, at least during growth in the bone marrow (BM) microenvironment.5 Thus, MM is an ideal model to test whether toxicity induced by iron could be exploited to control tumor progression.

To confirm the effect of excess iron in vivo, we injected U266 cells in Rag2−/−γc−/− immunodeficient mice, and when the disease expansion reached ~20% of BM tissue, we treated mice with a single intraperitoneal injection of iron dextran (250 mg/kg) or saline. Iron-treated mice showed a significantly increased (from 105 to 128 days; P<0.0001) median survival (Figure 1d) and a significantly lower U266 cell BM expansion compared with control mice. The latter was assessed by flow cytometry (Figure 1e) and by both morphological examination of BM sections (Supplementary Figures S1a and b) and immunostaining for CD138 and MUM-1 MM markers (Figure 1f). Notwithstanding increased inflammatory markers, liver expression of hepcidin, the master regulator of systemic iron homeostasis, was not upregulated in saline-treated mice, but, as expected, was strongly enhanced by iron2 (Supplementary Figures S1c and d). As for local iron distribution, we noticed that macrophages were iron positive in xenograft BM tissue (Figure 1g), as previously shown in BM of Vk*MYC model.5 Macrophage iron retention might be interpreted as the attempt of the immune system to induce malignant cells starvation. However, iron reduction might have the opposite effect in MM cells and translate into a prolonged survival by limiting ROS generation. Iron content further increased in BM macrophages of mice injected with iron (Figure 1g), although iron was mainly stored in the liver and spleen (Supplementary Figures S1e and f). Notwithstanding hepcidin-induced iron sequestration, we showed that also tumor cells have uptaken iron, by measuring a low iron regulatory protein activity, as an index of increased iron concentration in U266 cells isolated ex vivo from iron-treated xenograft mice (Figure 1h).

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Acknowledgements

We thank Giovanni Tonon for the valuable advice. This work was supported by AIRC-Fondazione Cariplo TRIDEO 2014 no. 15465 (to AC) and by AIRC Program Grant in Molecular Oncology-Extension no. 9965 (to AC).

Author contributions

JB performed research, analyzed results and contributed to writing the paper. SG and MTSB performed research. MP performed research and contributed to writing the paper. MC and PLB provided the Vk*MYC model, analyzed the data and contributed to writing the paper. CC contributed to the experimental design and to writing the paper. AC designed the experimental work, performed research and wrote the manuscript.

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Authors and Affiliations

  1. Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele,Milan, Italy

    J Bordini, S Galvan, C Camaschella & A Campanella

  2. Vita-Salute San Raffaele University, Milan, Italy

    J Bordini & C Camaschella

  3. Pathology and Myeloma Units, IRCCS Ospedale San Raffaele, Milan, Italy

    M Ponzoni

  4. Division of Molecular Oncology, IRCCS Ospedale San Raffaele, Milan, Italy

    M T S Bertilaccio

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

    M T S Bertilaccio

  6. Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ, USA

    M Chesi & P L Bergsagel

  7. Fondazione Centro San Raffaele, Milan, Italy

    A Campanella

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  1. J Bordini
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Correspondence to A Campanella.

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Bordini, J., Galvan, S., Ponzoni, M. et al. Induction of iron excess restricts malignant plasma cells expansion and potentiates bortezomib effect in models of multiple myeloma. Leukemia 31, 967–970 (2017). https://doi.org/10.1038/leu.2016.346

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