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

LARANJEIRA, Aba ; DE VASCONCELLOS, J. F ; SODEK, L ; SPAGO, M. C ; FORNAZIM, M. C ; TONE, L. G ; BRANDALISE, S. R ; NOWILL, A. E ; YUNES, J. A

Leukemia, 2012-05, Vol.26 (5), p.1001-1011 [Periódico revisado por pares]

Avenel, NJ: Nature Publishing Group

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IGFBP7 participates in the reciprocal interaction between acute lymphoblastic leukemia and BM stromal cells and in leukemia resistance to asparaginase
Autor: LARANJEIRA, Aba ; DE VASCONCELLOS, J. F ; SODEK, L ; SPAGO, M. C ; FORNAZIM, M. C ; TONE, L. G ; BRANDALISE, S. R ; NOWILL, A. E ; YUNES, J. A
Assuntos: Acute lymphoblastic leukemia ; Acute lymphocytic leukemia ; Analysis ; Asparaginase ; Asparaginase - pharmacology ; Asparagine ; Aspartate-ammonia ligase ; Beta cells ; Biological and medical sciences ; Bone marrow ; Bone Marrow Cells - pathology ; Case-Control Studies ; Cell adhesion & migration ; Cell culture ; Chemotherapy ; Child ; Child, Preschool ; Coculture Techniques ; Culture Media, Conditioned ; Drug resistance ; Drug Resistance, Neoplasm ; Drug therapy ; Female ; Flow Cytometry ; Gene Knockdown Techniques ; Genes ; Genetic aspects ; Growth factors ; Health aspects ; Hematologic and hematopoietic diseases ; Humans ; Infant ; Insulin ; Insulin-Like Growth Factor Binding Proteins - genetics ; Insulin-Like Growth Factor Binding Proteins - metabolism ; Insulin-Like Growth Factor Binding Proteins - physiology ; Insulin-like growth factors ; Leukemia ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Lymphatic leukemia ; Male ; Medical sciences ; mRNA ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology ; Precursors ; Recombinant Proteins - genetics ; Recombinant Proteins - metabolism ; Regression models ; RNA, Small Interfering ; Stromal cells ; Stromal Cells - pathology
É parte de: Leukemia, 2012-05, Vol.26 (5), p.1001-1011
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Descrição: 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.
Editor: Avenel, NJ: Nature Publishing Group
Idioma: Inglês

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

LARANJEIRA, Aba ; DE VASCONCELLOS, J. F ; SODEK, L ; SPAGO, M. C ; FORNAZIM, M. C ; TONE, L. G ; BRANDALISE, S. R ; NOWILL, A. E ; YUNES, J. A

Avenel, NJ: Nature Publishing Group

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