A DRUG SCREEN TO STUDY THE EFFECT OF EPIGENETIC INHIBITORS ON T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA CELLS
Author(s): ,
Cristina Prieto
Affiliations:
VIB Center for Cancer Biology,Leuven,Belgium;KU Leuven Center for Human Genetics,Leuven,Belgium
,
Michael Broux
Affiliations:
KU Leuven Center for Human Genetics,Leuven,Belgium;VIB Center for Cancer BIology,Leuven,Belgium
,
Sofie Demeyer
Affiliations:
VIB Center for Cancer BIology,Leuven,Belgium;KU Leuven Center for Human Genetics,Leuven,Belgium
,
Llucía Albertí-Servera
Affiliations:
VIB Center for Cancer BIology,Leuven,Belgium;KU Leuven Center for Human Genetics,Leuven,Belgium
,
Kris Jacobs
Affiliations:
KU Leuven Center for Human Genetics,Leuven,Belgium;VIB Center for Cancer Biology,Leuven,Belgium
Jan Cools
Affiliations:
VIB Center for Cancer Biology,Leuven,Belgium;KU Leuven Center for Human Genetics,Leuven,Belgium
EHA Library. Prieto Fernandez C. Jun 15, 2019; 267225; PS924
Cristina Prieto Fernandez
Cristina Prieto Fernandez
Contributions
Abstract

Abstract: PS924

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia resulting from the transformation of hematopoietic progenitors and accounting for 10-15% of pediatric and 25% of adult ALL cases. T-ALL cells are characterized by a deregulated gene expression caused by abnormal expression of transcription factors as well as mutations in various epigenetic factors. The use of intense chemotherapy regimens has improved T-ALL survival rates in the last decades, albeit at the expense of important short- and long-term side effects. In addition, the response of adult and relapsed cases is still very poor. There is therefore a need to further improve cure rates for adult T-ALL and to lower the toxicity of the chemotherapy treatments in children with T-ALL.  In this sense, epigenetics gain importance as potential drug treatments. Interestingly, some epigenetic drugs (HDAC inhibitors-HDACi-, DNA methyltransferase inhibitors-DNMTi-) have been already approved by the US Food and Drug Administration (FDA) for the treatment of hematological malignancies.

Aims

In this study, our aim was to analyze the effect of epigenetic drugs on T-ALL cell growth alone or in combination with chemotherapy or targeted therapies.

Methods

We performed a medium-throughput drug screen with a collection of 181 epigenetic drugs on 10 T-ALL cell lines at a fixed concentration (1uM). After 48h treatment, cell growth was measured using the ATP-lite Luminescence assay system and the percentage of viable cells was calculated in reference to non-treated cells (DMSO). Dose-response curves were performed to calculate the IC50 values for a selection of drugs. Apoptosis was measured based on Annexin V staining by flow cytometry and cell cycle was studied using the Click-iT EdU Alexa kit. Selected drugs were combined in vitro with currently used chemotherapeutic and targeted drugs and dose-response combination assays were analyzed using SynergyFinder web application (https://synergyfinder.fimm.fi) to search for synergistic combinations of drugs.

Results

The drug screen revealed a high efficiency of Class I-HDAC inhibitors and Pan-HDACi in inhibiting T-ALL cell growth in vitro. HDACi induced apoptosis and cell cycle arrest in S-phase on T-ALL cell lines. Together with currently used chemotherapeutic and targeted agents, HDACi (panobinostat and belinostat) showed a synergistic combination. By adding low concentrations of HDACi we were able to lower significantly the IC50 values of dexamethasone, KPT-8602, ruxolitinib, ABT-199, vincristine and doxorubicin. On the other hand, Aurora Kinase inhibitors (AKi) produced a heterogeneous effect on T-ALL. Among the 10 cell lines studied, we were able to distinguish good responders like ALLSIL cells, and non-responders like Jurkat cells. Our gene expression profile analysis revealed some genes correlated with AKi response (ROS pathway genes, mTOR signaling) and others correlated with AKi resistance (DNA repair, G2M checkpoint, KRAS signaling, UV response, NOTCH signaling).

Conclusion

Combination therapies including HDACi have been already tested for a wide range of tumors including breast cancer, and our results suggest that this approach can be also interesting for T-ALL treatment in order to lower the dose of highly toxic chemotherapy drugs. In addition, AKi demonstrated a strong cell growth inhibitory effect on a set of T-ALL cell lines defined by their gene expression profile. Further research is needed to find AKi response markers that can predict the effect of these epigenetic drugs on different T-ALL cases.

Session topic: 1. Acute lymphoblastic leukemia - Biology & Translational Research

Keyword(s): Drug sensitivity, Epigenetic, Histone deacetylase inhibitor, T-ALL

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