Functional G-CSF pathways in t(8;21) leukemic cells allow for differentiation induction and degradation of AML1-ETO

The Hematology Journal : the Official Journal of the European Haematology Association
N Da SilvaC Chomienne

Abstract

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. 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 chemothera...Continue Reading

Citations

Jun 30, 2004·Mediators of Inflammation·Lorena Lobo de FigueiredoEduardo Magalhães Rego
Sep 29, 2005·Hematology·Guang-Biao ZhouZhu Chen
Oct 3, 2002·Leukemia·P G LutzY E Cayre
May 13, 2005·Cancer Immunology, Immunotherapy : CII·Marie RobinRose-Ann Padua
Jun 17, 2008·Cytokine·Tamila L Kindwall-KellerBelinda R Avalos

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