Treatment with G-CSF reduces acute myeloid leukemia blast viability in the presence of bone marrow stroma.

Meritxell Nomdedeu,María Rozman,Marina Díaz-Beyá,Amaia Etxabe,Josep María Cornet-Masana,Dolors Costa,Jordi Esteve,María Carmen Lara-Castillo,Marta Pratcorona,Ruth M Risueño,Xavier Calvo

doi:10.1186/s12935-015-0272-3

Abstract

BackgroundThe resulting clinical impact of the combined use of G-CSF with chemotherapy as a chemosensitizing strategy for treatment of acute myeloid leukemia (AML) patients is still controversial. In this study, the effect of ex vivo treatment with G-CSF on AML primary blasts was studied.MethodsPeripheral blood mononuclear cells from AML patients were treated with G-CSF at increasing doses, alone or in co-culture with HS-5 stromal cells. Cell viability and surface phenotype was determined by flow cytometry 72 h after treatment. For clonogenicity assays, AML primary samples were treated for 18 h with G-CSF at increasing concentrations and cultured in methyl-cellulose for 14 days. Colonies were counted based on cellularity and morphology criteria.ResultsThe presence of G-CSF reduced the overall viability of AML cells co-cultured with bone marrow stroma; whereas, in absence of stroma, a negligible effect was observed. Moreover, clonogenic capacity of AML cells was significantly reduced upon treatment with G-CSF. Interestingly, reduction in the AML clonogenic capacity correlated with the sensitivity to chemotherapy observed in vivo.ConclusionsThese ex vivo results would provide a biological basis to data available from studies showing a clinical benefit with the use of G-CSF as a priming agent in patients with a chemosensitive AML and would support implementation of further studies exploring new strategies of chemotherapy priming in AML.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-015-0272-3) contains supplementary material, which is available to authorized users.

Highlights

The resulting clinical impact of the combined use of granulocyte colony-stimulating factor (G-CSF) with chemotherapy as a chemosensitizing strategy for treatment of acute myeloid leukemia (AML) patients is still controversial
In order to study the effect of G-CSF on cell viability, bulk AML blast population was treated with increasing doses of G-CSF
CXCR4 expression remained unaffected (Fig. 3b). These findings suggest that the cytotoxic effect of G-CSF on the AML blast population requires the presence of bone marrow microenvironment cells, and a direct contact with stroma cells

Summary

Introduction

The resulting clinical impact of the combined use of G-CSF with chemotherapy as a chemosensitizing strategy for treatment of acute myeloid leukemia (AML) patients is still controversial. According to the hierarchic model of cancer, AML cells are maintained by a subset of cells, called leukemic stem cells (LSCs), which have the capacity of self-renewal and differentiation [1]. Due to their stem cell–like properties, LSCs are the cell population showing a highest resistance to conventional chemotherapeutic agents used in AML treatment, such as anthracyclines and cytarabine [2]. The simultaneous administration of G-CSF and chemotherapy as a priming strategy has yielded conflicting results. Other studies have failed to show a clinical effect of priming strategies, these conflicting results must be due in part to different patient inclusion criteria, disease status and treatment administered [8, 9]

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