TARGETING ABERRANT DNA METHYLATION AS A NOVEL AND UNIFORM THERAPEUTIC STRATEGY FOR THE TREATMENT OF T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA AND LYMPHOMA
Author(s): ,
Morgan Thenoz
Affiliations:
Department of Biomolecular Medicine,Ghent University,Ghent,Belgium;Cancer Research Institute Ghent (CRIG),Ghent,Belgium
,
Juliette Roels
Affiliations:
Department of Biomolecular Medicine,Ghent University,Ghent,Belgium;Cancer Research Institute Ghent (CRIG),Ghent,Belgium
,
Lindy Reunes
Affiliations:
Department of Biomolecular Medicine,Ghent University,Ghent,Belgium;Cancer Research Institute Ghent (CRIG),Ghent,Belgium
,
Tim Pieters
Affiliations:
Department of Biomolecular Medicine,Ghent University,Ghent,Belgium;Cancer Research Institute Ghent (CRIG),Ghent,Belgium;VIB Inflammation Reserach Center,VIB-Ugent,Ghent,Belgium;Department for Biomedical Molecular biology,Ghent University,Ghent,Belgium
,
Sofie Peirs
Affiliations:
Department of Biomolecular Medicine,Ghent University,Ghent,Belgium;Cancer Research Institute Ghent (CRIG),Ghent,Belgium
,
Gloria Milani
Affiliations:
Department of Biomolecular Medicine,Ghent University,Ghent,Belgium;Cancer Research Institute Ghent (CRIG),Ghent,Belgium
,
Wouter Van Loocke
Affiliations:
Department of Biomolecular Medicine,Ghent University,Ghent,Belgium;Cancer Research Institute Ghent (CRIG),Ghent,Belgium
,
Tim Lammens
Affiliations:
Cancer Research Institute Ghent (CRIG),Ghent,Belgium;Department for Biomedical Molecular biology,Ghent University,Ghent,Belgium
,
Dieter Deforce
Affiliations:
Laboratory of Pharmaceutical Biotechnology,Ghent University,Ghent,Belgium
,
Filip Van Nieuwerburgh
Affiliations:
Laboratory of Pharmaceutical Biotechnology,Ghent University,Ghent,Belgium
,
Marc Mansour
Affiliations:
Department of Haematology,University College London Cancer Institute,London,United Kingdom
,
Tom Taghon
Affiliations:
Department of Diagnostic Sciences,Ghent University,Ghent,Belgium
,
Steven Gossens
Affiliations:
Department of Biomolecular Medicine,Ghent University,Ghent,Belgium;Cancer Research Institute Ghent (CRIG),Ghent,Belgium;VIB Inflammation Reserach Center,VIB-Ugent,Ghent,Belgium;Department for Biomedical Molecular biology,Ghent University,Ghent,Belgium
Pieter Van Vlierberghe
Affiliations:
Department of Biomolecular Medicine,Ghent University,Ghent,Belgium;Cancer Research Institute Ghent (CRIG),Ghent,Belgium
EHA Library. Thénoz M. Jun 15, 2019; 267443; S860
Morgan Thénoz
Morgan Thénoz
Contributions
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Abstract

Abstract: S860

Type: Oral Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 12:30 - 12:45

Location: Hall E103

Background

Genome-wide DNA methylation profiling studies have previously shown that T-cell acute lymphoblastic leukemia (T-ALL) patients can be classified into CpG island methylator phenotype (CIMP) positive and negative tumors. However, as these DNA methylation signatures have not been compared to corresponding profiles in subsets of normal human T cell precursors, it remains unclear if DNA methylation is uniformly perturbed in human T-ALL. Therefore, and given that molecular basis for these CIMP signatures remains largely unknown, DNA methylation inhibitors have not been extensively evaluated as a potential novel therapeutic strategy for human T-ALL.

Aims

In this study, we aimed to directly compare DNA methylation signatures between human T-ALLs and corresponding normal human T-cell precursors. In addition, we evaluated the potential role of Decitabine as a new therapeutic strategy for the treatment of human T-ALL and T-LBL.

Methods
DNA methylation profiling was performed by Illumina 850k EPIC arrays for human T-ALL (n=100) and normal T-cell subsets (n=22, 2 donors). T-ALL/T-LBL cell lines and patient derived xenografts in NSG mice were used for preclinical evaluation of Decitabine.

Results

Our analysis confirmed that human T-ALLs can be classified in CIMP+ and CIMP- T-ALLs based on DNA methylation signatures, and that this classification is strongly associated with genetic subtypes. Indeed, CIMP+ T-ALLs are enriched for immature, TLX and HOXA leukemias, whereas CIMP- cases mainly belong to the TAL-LMO rearranged subtype of human T-ALL. Given that each molecular genetic subtype is linked to a specific T-cell differentiation arrest, we wondered whether CIMP status would merely be a reflection of T-cell maturation and/or cell of origin. However, and most notably, integration of these data with DNA methylation signatures obtained from 11 different subsets along the T-cell differentiation trajectory, revealed that DNA methylation profiles from both CIMP+ and CIMP- T-ALLs are strongly perturbed as compared to all their normal T-cell counterparts. Indeed, human T-ALLs uniformly display a DNA hypermethylation phenotype as compared to their normal counterpart and putative cell of origin.

Given this, we wondered if targeting aberrant DNA methylation could serve as a uniform therapeutic strategy for both CIMP+ and CIMP- human T-ALLs. To evaluate this, we used a xenograft model of luciferase-positive LOUCY cells and showed that Decitabine treatment caused a marked reduction in bioluminescence with a concomitant loss of leukemic blasts in peripheral blood and a significant increase in leukemia free survival. Next, we used patient derived xenograft models from 6 different T-ALL/T-LBL patients  (different genetic subtypes, CIMP+ and CIMP- and including one relapse) to show that Decitabine treatment resulted in a significant increase in leukemia free survival for all samples analyzed (log-rank test, p<0,05).

Finally we used human T-ALL cell lines to investigate the molecular effects of 48h Decitabine treatment. As expected Decitabine treatment was associated with a decreased in total DNA 5mC levels and induced up-regulation and down-regulation of 1623 and 452 genes, respectively (padj<0,005, absolute Fc > 1,25). Enrichment analysis revealed that Decitabine most prominently caused downregulation of MYC and E2F gene signatures.

Conclusion
All together, our data suggest that human T-ALL samples are uniformly characterized by aberrant DNA methylation signatures and that Decitabine might serve as a promising and uniform novel therapeutic strategy for all genetic subtypes of human T-ALL and T-LBL.

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

Keyword(s): Decitabine, DNA methylation, T-ALL

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