Bone marrow stroma modulates the expression of several drug resistance/sensitivity genes in pediatric acute limphoblastic leukemia / O estroma da medula ossea e a sua influencia na expressão de genes de resistencia e sensibilidade a quimioterapicos na leucemia linfoide aguda (LLA) pediatrica

AUTOR(ES)
DATA DE PUBLICAÇÃO

2007

RESUMO

The intrinsic or acquired chemotherapy resistance composites one of the most important causes of failures in the treatment of pediatric ALL. The ALL and bone marrow microenvironment nteraction contributes for the proliferation and resistance to the chemotherapy regimen of leukemic cells probably through a great variety of cellular mechanisms, including increase of the expression of cellular transporters, increase in the process of DNA repair, downregulation of drugs targets, changes in the regulation of cellular cycle and alteration in the apoptotic ways. In the present study it was observed that the interaction established between stromal cells and pre-B ALL, evaluated through analysis of surface molecules in leukemic cells throughout the periods of culture, were important for the survival and/or proliferation in more than 50% of the cases in vitro. This interaction also showed the influence of stroma in the transcriptional profile of 17 genes related with the resistance and sensitivity to chemotherapeutic agents in pre-B ALL cells. The modulation had as consequence the increase in the levels of expression of the majority of the resistance genes and the decrease of expression of the majority of the sensitivity genes. Being thus, these cellular types, for the interaction with the stromal cells, had presented an alteration that took them to one phenotype characteristic of resistant cells. This stroma-mediated alteration was confirmed by functional studies of two genes related with the resistance. Gene KCNN4 three leukemic cell lines, that when submitted to the action of clotrimazole they had presented greater viability in the presence than in the absence of stroma; and the addition of recombinant protein IGFBP-7 in the co-culture system promoted the resistance and proliferation of primary ALL cells in the presence of the L-asparaginase. This protein also induced proliferation of stromal cells. These results show two genes of ALL, that when modulated for the contact with stroma, can contribute with a resistance to the chemotherapic regimen, becoming possible targets for posterior therapies

ASSUNTO(S)

acute lymphocytic leukemia human igfbp7 gene drug resistance bone marrow stroma tumour microenvironment drogas - resistencia leucemia linfocitica aguda estroma da medula ossea microambiente tumoral gene igfbp7 humano

ACESSO AO ARTIGO

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