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Inhibition of precursor B-cell malignancy progression by toll-like receptor ligand-induced immune responses

Leukemia volume 30, pages 2116–2119 (2016)Cite this article

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The interaction between infection and pediatric acute lymphoblastic leukemia (ALL) has been a focus of epidemiologic study for over 50 years. Although a protective effect against ALL has often been reported when surrogates of infection exposure, such as day care attendance, were analyzed,1 studies of documented early infections indicated a subsequent increased risk of ALL.2 A mechanistic explanation for these apparently contradictory findings has yet to be provided. The demonstration that a leukemia-initiating cell (LIC) for pediatric B-cell precursor (BCP) ALL frequently arises in utero has defined an extended pre-leukemic phase during which immune modulation could influence subsequent disease progression.3, 4, 5 Consistent with this hypothesis, delayed exposure to multiple infections increased leukemia penetrance in Pax5 heterozygous mice.6 A toll-like receptor (TLR) 4-driven upregulation of intrinsic mutagenic activity was proposed as a potential in vivo driver of this leukemogenesis, based on its contribution to the transformation of ETV6-RUNX1-transduced pre-B cells.7 However, the potentially opposing impact of the induced immune response on the overall outcome of such inflammatory stimulation has not been evaluated. Here, we used the Eμ-ret8, 9 and E2A-PBX110 transgenic mouse models of BCP ALL malignancy to investigate the influence of TLR ligation on LIC fate.

The impact of changes in their immune environment on LIC is likely to be influenced by their lineage and stage of differentiation arrest. Although, importantly, Eμ-ret mice consistently present with a leukemia arrested at the stage of B-cell differentiation observed most often in pediatric ALL, RET is not a recognized driver of clinical disease. This raises the possibility that the observed depletion may be specific for LIC generated by this oncogene. To address this directly, we compared effects on Eμ-ret-derived LIC to those achieved with LIC generated in a multistep ALL model driven by the clinically relevant E2A-PBX1 translocation (Figure 1c).10 When cultured on NSG bone marrow, LIC from Eμ-ret and Tg(E2A-PBX1) Pax+/− Cd19-Cre mice yielded a similar pattern of TLR-induced depletion. This result confirms the generality of the depletion response to distinct LIC populations and validates the Eμ-ret model for studies of immune influences on LIC survival and ALL progression.

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Acknowledgements

This work was supported by grants to GSDR from the Prevent Cancer Foundation, When Everyone Survives Foundation, Michael Cuccione Foundation and Canadian Institutes of Health Research (CIH; MOP-126122) and a Career Development Award in Prevention from the Canadian Cancer Society. Also supported in part by the American Society of Blood and Marrow Transplantation Robert A. Good Young Investigator Award, Helpful Gifts from the Heart Foundation, and American Cancer Society Mentored Research Scientist Grant in Applied and Clinical Research, MRSG-12-215-01-LIB (AES); a CFRI Graduate Studentship (MF); a NCI F31 Pre-doctoral Fellowship CA177092 and Training Grant TG GM-07229 of the University of Pennsylvania (AD); a CIHR fellowship grant (NR), a Cancer Research Institute Pre-doctoral Emphasis Pathway in Tumor Immunology Training Grant of the University of Pennsylvania (BY); a Leukemia and Lymphoma Society Scholar Award and NIH grant CA125195 (CHB); and NIH grants R01CA102646, R01CA116660 and support from the Weinberg Foundation (SAG); the German Research Foundation (Deutsche Forschungsgemeinschaft, ref DU 1287/2-1) (JD-A); and the Lucile Packard Foundation for Children’s Health, the Child Health Research Institute and the Stanford NIH-NCATS-CTSA grant #UL1 TR001085 (MLC and JD-A).

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Author notes

  1. M Fidanza and A E Seif: These authors contributed equally to this work.

Authors and Affiliations

  1. Michael Cuccione Childhood Cancer Research Program, Child and Family Research Institute, Vancouver, British Columbia, Canada

    M Fidanza, N Rolf, S Jo & G S D Reid

  2. Center for Childhood Cancer Research, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    A E Seif, A DeMicco, B Yin, Y Li, D M Barrett, C H Bassing & S A Grupp

  3. Department of Pediatrics, Division of Oncology, University of Pennsylvania, Philadelphia, PA, USA

    A E Seif, Y Li, D M Barrett & S A Grupp

  4. Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA

    A E Seif, A DeMicco, B Yin, C H Bassing & S A Grupp

  5. Department of Pathology and Laboratory Medicine, Division of Cancer Pathobiology, University of Pennsylvania, Philadelphia, PA, USA

    A DeMicco, B Yin & C H Bassing

  6. Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada

    N Rolf & G S D Reid

  7. Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA,

    Y Li

  8. Department of Pathology, School of Medicine, Stanford University, Stanford, CA, USA

    J Duque-Afonso & M L Cleary

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  1. M Fidanza
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Correspondence to G S D Reid.

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Fidanza, M., Seif, A., DeMicco, A. et al. Inhibition of precursor B-cell malignancy progression by toll-like receptor ligand-induced immune responses. Leukemia 30, 2116–2119 (2016). https://doi.org/10.1038/leu.2016.152

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