An immediate transcriptional signature associated with response to the histone deacetylase inhibitor Givinostat in T acute lymphoblastic leukemia xenografts.

M Pinazza,A Amadori,B Michielotto,C Borga,V Agnusdei,S Indraccolo,M Paganin,G Te Kronnie,S Minuzzo,A De Paoli,G Basso,G Fossati

doi:10.1038/cddis.2015.394

Abstract

Despite some success with certain hematological malignancies and in contrast with the strong pro-apoptotic effects measured in vitro, the overall response rate of acute lymphoblastic leukemia (ALL) to histone deacetylase inhibitors (HDACis) is low. With the aim to improve the understanding of how HDACis work in vivo, we investigated the therapeutic efficacy of the clinically approved HDACi Givinostat in a collection of nine pediatric human T-ALL engrafted systemically in NOD/SCID mice. We observed highly heterogeneous antileukemia responses to Givinostat, associated with reduction of the percentage of infiltrating blasts in target organs, induction of apoptosis and differentiation. These effects were not associated with the T-ALL cytogenetic subgroup. Transcriptome analysis disclosed an immediate transcriptional signature enriched in genes involved in cell-cycle regulation and DNA repair, which was validated by quantitative RT-PCR and was associated with in vivo response to this HDACi. Increased phospho-H2AX levels, a marker of DNA damage, were measured in T-ALL cells from Givinostat responders. These results indicate that the induction of the DNA damage response could be an early biomarker of the therapeutic effects of Givinostat in T-ALL models. This information should be considered in the design of future clinical trials with HDACis in acute leukemia.

Highlights

Inhibitors (HDACis) have various antitumor effects and have been shown to promote apoptosis, induce cell-cycle arrest and differentiation of tumor cells,[1,2] as well as to exert therapeutic activity in preclinical tumor models.[3,4] In patients, histone deacetylase inhibitor (HDACi) have demonstrated therapeutic potential for some hematological malignancies, including myelodysplastic syndromes, relapsed non-Hodgkin’s lymphoma and mantle-cell lymphoma.[5]
To evaluate the therapeutic activity of HDACis in the contest of T-cell acute lymphoblastic leukemia (T-ALL), we initially set up a mouse trial with a panel of nine patient-derived xenografts, previously established from pediatric T-ALL samples in nonobese diabetic/severe combined immunodeficiency mice (NOD/SCID mice).[19]
Key clinical and genetic features of these xenografts and the donor’s T-ALL, such as cytogenetic subgroup, prednisone sensitivity and minimal residual disease (MRD) risk are reported in Table 1; the diagnostic immunophenotype is shown in Supplementary Table SIV

Summary

Introduction

Inhibitors (HDACis) have various antitumor effects and have been shown to promote apoptosis, induce cell-cycle arrest and differentiation of tumor cells,[1,2] as well as to exert therapeutic activity in preclinical tumor models.[3,4] In patients, HDACis have demonstrated therapeutic potential for some hematological malignancies, including myelodysplastic syndromes, relapsed non-Hodgkin’s lymphoma and mantle-cell lymphoma.[5]. In a recent preclinical study, it was shown that endothelial cells provide a Notch-dependent pro-tumoral niche for enhancing B-cell lymphoma survival and chemoresistance.[16] Possibly, similar microenvironment-related mechanisms could contribute to attenuate the pro-apoptotic effects of HDACis, limiting therapeutic effects in some individuals. Based on these considerations, when designing this study we considered mandatory to perform in vivo experiments with

Methods

Results

Conclusion