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Acute Leukemias

Absence of IL-12Rβ2 in CD33+CD38+ pediatric acute myeloid leukemia cells favours progression in NOD/SCID/IL2RγC-deficient mice

Leukemia volume 26, pages 225–235 (2012)Cite this article

Abstract

Childhood acute myeloid leukemia (AML) is a hematological malignancy in which tumor burden is continuously replenished by leukemic-initiating cells (ICs), which proliferate slowly and are refractory to chemotherapeutic agents. We investigated whether interleukin (IL)-12, an immuno-modulatory cytokine with anti-tumor activity, may target AML blasts (CD45+CD33+) and populations known to contain leukemia ICs (that is, CD34+CD38−, CD33+CD38+ and CD44+CD38− cells). We demonstrate for the first time that: i) AML blasts and their CD34+CD38−, CD33+CD38+, CD44+CD38− subsets express the heterodimeric IL-12 receptor (IL-12R), ii) AML cells injected subcutaneously into NOD/SCID/Il2rg−/− (NSG) mice developed a localized tumor mass containing leukemic ICs and blasts that were virtually eliminated by IL-12 treatment, iii) AML cells injected intravenously into NSG mice engrafted within the first month in the spleen, but not in bone marrow or peripheral blood. At this time, IL-12 dramatically dampened AML CD45+CD33+, CD34+CD38−, CD33+CD38+ and CD44+CD38− populations, only sparing residual CD33+CD38+ cells that did not express IL-12Rβ2. From 30 to 60 days after the initial inoculum, these IL-12-unresponsive cells expanded and metastasized in both control and IL-12-treated NSG mice. Our data indicate that the absence of IL-12Rβ2 in pediatric AML cells favours leukemia progression in NOD/SCID/IL2Rγc-deficient mice.

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Acknowledgements

This work was supported by grants from the Associazione Italiana Ricerca sul Cancro (AIRC) Milano, Italy (Grant number 4014 to IA), the Italian Ministry of Health (RF, RC, 5/1000, Progetto Strategico Oncologico 2006 rif070701) and the Fondazione Cassa di Risparmio della Provincia di Chieti (CariChieti), Italy to EDC; by grants from AIRC to VP; by the special grant 5 per mille from AIRC to FL; and grant from the Fondazione IRCCS Policlinico San Matteo Pavia Ricerca Corrente to DM. Wyeth, Cambridge, MA is acknowledged for the kindly gift of human recombinant IL-12.

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Author notes

  1. V Pistoia and I Airoldi: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Oncology, G. Gaslini Institute, Genova, Italy

    E Ferretti & V Pistoia

  2. Department of Pediatrics, University of Pavia, Foundation IRCCS Policlinico, Pavia, Italy

    D Montagna & F Locatelli

  3. Department of Oncology and Neurosciences, ‘G. d'Annunzio’ University and Ce.S.I. Aging Research Center, ‘G. d'Annunzio’ University Foundation, Chieti, Italy

    E Di Carlo & C Sorrentino

  4. Department of Experimental and Laboratory Medicine, AIRC Laboratory of Immunology and Tumors, G. Gaslini Institute, Genova, Italy

    C Cocco & I Airoldi

  5. Department of Human Anatomy and Histology, University of Bari, Bari, Italy

    D Ribatti

  6. Animal Model Facility, National Institute for Cancer Research, Genova, Italy

    E Ognio

  7. Pediatric Hematology and Oncology, Fondazione, IRCCS Policlinico San Matteo, Pavia, Italy

    D Lisini

  8. Department of Pediatric Hematology and Oncology, IRCCS, Bambino Gesù Hospital, Roma, Italy

    A Bertaina & F Locatelli

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Correspondence to I Airoldi.

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Ferretti, E., Montagna, D., Di Carlo, E. et al. Absence of IL-12Rβ2 in CD33+CD38+ pediatric acute myeloid leukemia cells favours progression in NOD/SCID/IL2RγC-deficient mice. Leukemia 26, 225–235 (2012). https://doi.org/10.1038/leu.2011.213

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