Program DHC-Virtual
20 - 21 January 2021
Abstracts Myeloid session 4
Abstract
Targeting histone methylation to overrule transcriptionally driven drug resistance
21 January
10:36 10:48
N. van Gils
Paper

Targeting histone methylation to overrule transcriptionally driven drug resistance in myeloid leukemia

Noortje van Gils (1), Han Verhagen (1), Tània Martiáñez (1), Fedor Denkers (1), Eline Vermue (1), Arjo Rutten (1), Tamás Csikós (1), Meyram Çil (1), Marjon Al (1), Frank van Gemert (1), Jeroen Janssen (1), Gert Ossenkoppele (1), Renee Menezes (2), Linda Smit (1)
(1) Amsterdam UMC, location VUmc, Hematology, Amsterdam, (2) Amsterdam UMC, location VUmc, Epidemiology and Biostatistics, Amsterdam
No potential conflicts of interest
Introduction

Standard induction chemotherapy, consisting of an anthracycline and cytarabine, has been the first-line therapeutic to treat acute myeloid leukemia (AML). Although this treatment induces complete remissions (CR) in the majority of patients, many face a relapse. Relapse is caused by the survival of chemotherapy-resistant leukemia cells (minimal residual disease, MRD), that may have acquired drug resistance by non-genetic mechanisms. Persistence of MRD is driven by intra-leukemic heterogeneity and plasticity in response to therapy. Leukemia cells within MRD capable of initiating relapse are thought to have stem cell features and are therefore named “leukemic stem cells” (LSCs).

Methods

In this study, we demonstrated that the anthracycline doxorubicin epigenetically reprograms leukemia cells by inducing tri-methylation of histone 3 lysine 27 (H3K27) and H3K4. Moreover, to understand chemotherapy resistance at the single-cell level and to study intra-leukemia heterogeneity with respect to anthracycline sensitivity, we seeded K562 myeloid leukemia cells in 480 wells, each containing 10.000 cells, and treated the cells with increasing concentrations of doxorubicin.

Results

Using this approach, a subpopulation of reversible anthracycline-tolerant cells (ATCs) was identified within the doxorubicin-sensitive leukemia cell population, which lacked upregulation of H3K27me3 or H3K4me3 and exhibited epigenetically regulated expression of stem cell features similar to LSCs. These ATCs have a distinct transcriptional landscape from the leukemia bulk and could be eradicated by the KDM6 inhibitor GSK-J4. In primary human AML, GSK-J4 treatment could eliminate AML blasts and LSCs at diagnosis, but importantly it could significantly reduce chemotherapy resistant AML patient cell load (MRD) and survival of LSCs residing within MRD, ex vivo and in vivo. An efficient response to GSK-J4 was associated with upregulation of H3K27 and/or H3K4 methylation, and downregulation of STAT5B. 

Conclusion

Together, our results reveal plasticity of anthracycline resistance in AML cells and highlight the potential of epigenetic-based therapeutics to target chemotherapy-resistant AML cells. 

×