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Sensitivity and Resistance to Therapy

IGFBP7 participates in the reciprocal interaction between acute lymphoblastic leukemia and BM stromal cells and in leukemia resistance to asparaginase

Leukemia volume 26, pages 1001–1011 (2012)Cite this article

Abstract

The interaction of acute lymphoblastic leukemia (ALL) blasts with bone marrow (BM) stromal cells (BMSCs) has a positive impact on ALL resistance to chemotherapy. We investigated the modulation of a series of putative asparaginase-resistance/sensitivity genes in B-precursor ALL cells upon coculture with BMSCs. Coculture with stromal cells resulted in increased insulin-like growth factor (IGF)-binding protein 7 (IGFBP7) expression by ALL cells. Assays with IGFBP7 knockdown ALL and stromal cell lines, or with addition of recombinant rIGFBP7 (rIGFBP7) to the culture medium, showed that IGFBP7 acts as a positive regulator of ALL and stromal cells growth, and significantly enhances in-vitro resistance of ALL to asparaginase. In these assays, IGFBP7 function occurred mainly in an insulin- and stromal-dependent manner. ALL cells were found to contribute substantially to extracellular IGFBP7 levels in the conditioned coculture medium. Diagnostic BM plasma from children with ALL had higher levels of IGFBP7 than controls. IGFBP7, in an insulin/IGF-dependent manner, enhanced asparagine synthetase expression and asparagine secretion by BMSCs, thus providing a stromal-dependent mechanism by which IGFBP7 protects ALL cells against asparaginase in this coculture system. Importantly, higher IGFBP7 mRNA levels were associated with lower leukemia-free survival (Cox regression model, P=0.003) in precursor B-cell Ph(−) ALL patients (n=147) treated with a contemporary polychemotherapy protocol.

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Acknowledgements

This work was supported by grants from FAPESP 08/10034-1 and CNPq 401122/05 to JAY and FAPESP 05/50731-5 to LGT. ABAL was supported by FAPESP 08/02106-2 and JFV was supported by FAPESP 06/01158-3. We especially acknowledge the contribution of patients and their families.

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Authors and Affiliations

  1. Centro Infantil Boldrini, Laboratório de Biologia Molecular, Campinas, SP, Brazil

    A B A Laranjeira, J F de Vasconcellos, S R Brandalise & J A Yunes

  2. Departamento de Biologia Vegetal, Universidade Estadual de Campinas, Campinas, SP, Brazil

    L Sodek

  3. Centro Integrado de Pesquisas Oncohematológicas da Infância, Universidade Estadual de Campinas, Campinas, SP, Brazil

    M C Spago, M C Fornazim & A E Nowill

  4. Department of Pediatrics, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Child Care and Pediatry, Ribeirão Preto, SP, Brazil

    L G Tone

  5. Departamento de Pediatria, Universidade Estadual de Campinas, Campinas, SP, Brazil

    S R Brandalise

  6. Departamento de Genética Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil

    J A Yunes

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  1. A B A Laranjeira
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Laranjeira, A., de Vasconcellos, J., Sodek, L. et al. IGFBP7 participates in the reciprocal interaction between acute lymphoblastic leukemia and BM stromal cells and in leukemia resistance to asparaginase. Leukemia 26, 1001–1011 (2012). https://doi.org/10.1038/leu.2011.289

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