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Nurse-like cells control the activity of chronic lymphocytic leukemia B cells via galectin-1

Leukemia volume 27, pages 1413–1416 (2013)Cite this article

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Chronic lymphocytic leukemia (CLL) cells are preferentially activated in so-called proliferation centers frequently found in lymph nodes and bone marrow from CLL patients.1 In these ‘privileged’ sites leukemic cells establish close contact with a variety of cell types that provide long-term support for their survival and progression. In addition, CLL cells favor the establishment of immunosuppressive microenvironments by altering the cytokine milieu.2 Galectin 1 (Gal1), an endogenous β-galactoside-binding lectin found at sites of inflammation and tumor growth, displays pro-survival activity on malignant cells as demonstrated for CD45RA(−) primary myeloma cells.3 Moreover, it controls tumor cell proliferation and invasiveness and has key roles in tumor-immune escape by dampening T-cell-mediated immunity.4 In Hodgkin lymphoma, Gal1 is overexpressed in Reed–Sternberg cells, which is a predictive biomarker of disease progression and is responsible for creating the Th2/regulatory T-cell-skewed microenvironment typical of this lymphoproliferative disease.5 These unique characteristics of Gal1 prompted us to investigate its potential role in CLL biology.

In the presence of leukemic cells, monocytes from CLL patients can differentiate in vitro into large, adherent cells that protect the leukemic clone from spontaneous and drug-induced apoptosis. These so-called nurse-like cells (NLC) reside in lymphoid tissues where they presumably deliver pro-survival and stimulating signals to CLL cells.6 To determine whether Gal1 secreted by myeloid cells can influence leukemic B-cells responses, we knocked down Gal1 synthesis in NLC. For this purpose, we differentiated NLC from peripheral blood CLL samples as previously described,7 removed non-adherent cells (>90% leukemic B cells) and transduced adherent NLC with retrovirus expressing Gal1-specific short hairpin RNA (shRNA) or a scrambled control shRNA (Figures 1e and f). After 6 h of incubation, transduced NLC were thoroughly washed and non-adherent cells were incorporated to the plates for further co-culture. Thereafter, we evaluated in the leukemic clone expression of the activation markers CD80, CD86 and CD25, production of IL-10 as a prototypical anti-inflammatory cytokine and synthesis of CCL3 and CCL4 as key chemokines responsible for the recruitment of monocytes and T lymphocytes to lymphoid tissues. We found that blockade of Gal1 in NLC impaired the expression of activation markers in CLL cells, suggesting that the presence of endogenous Gal1 in myeloid cells is required for full stimulation of the leukemic clone (Supplementary Figure S1). Blockade of Gal1 also decreased mRNA and protein levels of IL-10 and mRNA levels of CCL3 in CLL cells, without affecting those of CCL4 (Figures 1g and h). Although previous reports showed that recombinant Gal1 induces the release of IL-10 from activated T lymphocytes and dendritic cells,8 there is still no information on its effects on CCL3. Of note, both IL-10 and CCL3, are relevant in CLL pathogenesis as their serum concentrations are elevated in CLL patients9, 10 and, more importantly, they correlate with shorter time-to-first treatment and survival.11

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Acknowledgements

This work was supported by grants from the National Council of Scientific and Technical Research (CONICET; Argentina), National Agency for Promotion of Science and Technology (Argentina), University of Buenos Aires and Fundación Sales (Argentina).

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Author notes

  1. G A Rabinovich and M Giordano: GA Rabinovich and M Giordano share senior authorship

Authors and Affiliations

  1. Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad de Buenos Aires, Argentina

    D O Croci, S Dergan-Dylon, M A Toscano, J C Stupirski & G A Rabinovich

  2. Laboratorio de Inmunología Oncológica, Instituto de Investigaciones Médicas (IMEX/CONICET), Academia Nacional de Medicina, Ciudad de Buenos Aires, Argentina

    P E Morande, M Borge, M Narbaitz, R Gamberale & M Giordano

  3. Hospital General de Agudos ‘Dr T. Alvarez’, Ciudad de Buenos Aires, Argentina

    R F Bezares

  4. Hospital de Clínicas ‘José de San Martín’, Ciudad de Buenos Aires, Argentina

    J S Avalos

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  1. D O Croci
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Correspondence to M Giordano.

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Croci, D., Morande, P., Dergan-Dylon, S. et al. Nurse-like cells control the activity of chronic lymphocytic leukemia B cells via galectin-1. Leukemia 27, 1413–1416 (2013). https://doi.org/10.1038/leu.2012.315

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