Functional G-CSF pathways in t(8;21) leukemic cells allow for differentiation induction and degradation of AML1-ETO
| Autor: | Nicole Balitrand, Alyssa Lebel, Laurent Degos, J.M. Miclea, M L Menot, Hervé Dombret, Da Silva N, Pierre Fenaux, Christine Chomienne, Antonio Parrado, Rousselot P, Sandrine Meyer-Monard |
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| Rok vydání: | 2000 |
| Předmět: |
STAT3 Transcription Factor
Oncogene Proteins Fusion Chromosomes Human Pair 21 CD34 Apoptosis Bone Marrow Cells Tretinoin CD15 Translocation Genetic RUNX1 Translocation Partner 1 Protein Antigen In vivo Antigens CD Granulocyte Colony-Stimulating Factor Tumor Cells Cultured Humans Blood Cells Chemistry Cell Differentiation Hematology Fusion protein In vitro Recombinant Proteins Cell biology Neoplasm Proteins DNA-Binding Proteins Haematopoiesis Leukemia Myeloid Acute STAT1 Transcription Factor Cell culture Core Binding Factor Alpha 2 Subunit Receptors Granulocyte Colony-Stimulating Factor Trans-Activators Chromosomes Human Pair 8 Signal Transduction Transcription Factors |
| Zdroj: | Scopus-Elsevier |
| ISSN: | 1466-4860 |
| Popis: | INTRODUCTION Efficacy of differentiating agents requires that their specific cellular targets are still expressed and functional in the leukemic cells. One hypothesis to target sensitive cells is to select leukemic clones which harbor disrupted transcription factors. CBFalpha and CBFbeta are core-binding proteins which have been identified as transcription regulators of hematopoietic genes and shown to be altered in numerous leukemias. In M2 AML, the t(8;21) translocation, CBFalpha (AML1) is altered and produced as the AML1-ETO fusion protein. The fusion protein blocks transcription and differentiation mediated by G-CSF. Interestingly, AML1-ETO leukemic cell lines are sensitive to numerous cytokines in vitro and can be induced to differentiate in the presence of G-CSF and PMA. MATERIALS AND METHODS As in the APL differentiation model, primary culture provides a useful tool for therapeutic screening of differentiation inducers, we analysed the in vitro sensitivity of 10 fresh M2 AML t(8;21) leukemic samples to G-CSF and the functionality of G-CSF intracellular pathways. In vitro data were compared with in vivo data from four patients treated with rhG-CSF at the dosage of 5 microg/kg/day i.v. for two to three weeks before the initiation of AML induction chemotherapy and immunophenotypic analysis performed weekly to monitor in vivo differentiation. RESULTS In vitro, an increase in CD34+ cells expressing differentiation antigens (CD11b, CD13 or CD15) was noted along with a decrease of immature CD34+/differentiation antigen negative cells. After two weeks of a daily rhG-CSF administration in vivo, a significant, albeit transient, decrease of blast count was achieved, concomitant with an increase in differentiated leukemic cells suggesting that in vivo differentiation occurs. Fresh t(8;21) leukemic cells possess functional G-CSF signaling pathways as normal activity and kinetics of STAT1 and STAT3 binding was observed. Furthermore, differentiation induction leads to a subsequent degradation of the AML1-ETO oncoprotein. CONCLUSION The data presented here supports the claim that G-CSF can induce in vitro and in vivo differentiation of M2 AML t(8;21) cells. |
| Databáze: | OpenAIRE |
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