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

Autor(es)

Laranjeira, A. B. A. ^[1] ; de Vasconcellos, J. F. ^[1] ; Sodek, L. ^[2] ; Spago, M. C. ^[3] ; Fornazim, M. C. ^[3] ; Tone, L. G. ^[4] ; Brandalise, S. R. ^{[1, 5]} ; Nowill, A. E. ^[3] ; Yunes, J. A. ^{[1, 6]}

Afiliação do(s) autor(es)

^[1] Ctr Infantil Boldrini, Mol Biol Lab, BR-13083210 Campinas, SP - Brazil

^[2] Univ Estadual Campinas, Dept Biol Vegetal, Campinas, SP - Brazil

^[3] Univ Estadual Campinas, Ctr Integrado Pesquisas Oncohematol Infancia, Campinas, SP - Brazil

^[4] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Pediat, Ribeirao Preto, SP - Brazil

^[5] Univ Estadual Campinas, Dept Pediat, Campinas, SP - Brazil

^[6] Univ Estadual Campinas, Fac Ciencias Med, Dept Med Genet, Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: LEUKEMIA; v. 26, n. 5, p. 1001-1011, MAY 2012.
• Citações Web of Science: 15

Resumo

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. (AU)

• Processo FAPESP: 08/10034-1 - Microambiente da medula óssea e PI3K na resistência a drogas da leucemia linfóide aguda pediátrica
• Beneficiário: José Andrés Yunes
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 05/50731-5 - Estudo do padrão da expressão de genes relacionados à resistência/sensibilidade aos quimioterápicos na leucemia linfóide aguda da criança e do adolescente
• Beneficiário: Luiz Gonzaga Tone
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 06/01158-3 - Ação da CCL2 na sobrevivência e proliferação da leucemia linfóide aguda pediátrica, em sistema de co cultura com células do estroma da medula óssea
• Beneficiário: Jaíra Ferreira de Vasconcellos
• Linha de fomento: Bolsas no Brasil - Doutorado
• Processo FAPESP: 08/02106-2 - IGFBP7 e a quimioresistência da leucemia linfóide aguda pediátrica
• Beneficiário: Angelo Brunelli Albertoni Laranjeira
• Linha de fomento: Bolsas no Brasil - Doutorado