| Full text | |
| Author(s): |
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.
[5, 1]
;
Nowill, A. E.
[3]
;
Yunes, J. A.
[6, 1]
Total Authors: 9
|
| Affiliation: | [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
Total Affiliations: 6
|
| Document type: | Journal article |
| Source: | LEUKEMIA; v. 26, n. 5, p. 1001-1011, MAY 2012. |
| Web of Science Citations: | 14 |
| 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. (AU) | |
| FAPESP's process: | 08/02106-2 - IGFBP7 role in chemotherapy resistance of Pediatric Acute Lymphoblastic Leukemia |
| Grantee: | Angelo Brunelli Albertoni Laranjeira |
| Support type: | Scholarships in Brazil - Doctorate |
| FAPESP's process: | 08/10034-1 - Bone marrow microenvironment and PI3K pathway in resistance to chemotherapy of pediatric acute lymphoblastic leukemia |
| Grantee: | José Andrés Yunes |
| Support type: | Regular Research Grants |