Targeting histone methylation to reprogram the transcriptional state that drives survival of drug-tolerant myeloid leukemia persisters

Noortje van Gils; Han J M P Verhagen; Michaël Broux; Tania Martiáñez; Fedor Denkers; Eline Vermue; Arjo Rutten; Tamás Csikós; Sofie Demeyer; Meryem Çil; Marjon Al; Jan Cools; Jeroen J W M Janssen; Gert J Ossenkoppele; Renee X Menezes; Linda Smit

doi:10.1016/j.isci.2022.105013

Targeting histone methylation to reprogram the transcriptional state that drives survival of drug-tolerant myeloid leukemia persisters

iScience. 2022 Aug 25;25(9):105013. doi: 10.1016/j.isci.2022.105013. eCollection 2022 Sep 16.

Authors

Noortje van Gils¹, Han J M P Verhagen¹, Michaël Broux^{2

3}, Tania Martiáñez¹, Fedor Denkers¹, Eline Vermue¹, Arjo Rutten¹, Tamás Csikós¹, Sofie Demeyer^{2

3}, Meryem Çil¹, Marjon Al¹, Jan Cools^{2

3}, Jeroen J W M Janssen¹, Gert J Ossenkoppele¹, Renee X Menezes⁴, Linda Smit¹

Affiliations

¹ Department of Hematology, Amsterdam UMC, location VUmc, Cancer Center Amsterdam, Amsterdam, the Netherlands.
² KU Leuven Center for Human Genetics, Leuven, Belgium.
³ VIB Center for Cancer Biology, Leuven, Belgium.
⁴ Department of Epidemiology and Biostatistics, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands.

Abstract

Although chemotherapy induces complete remission in the majority of acute myeloid leukemia (AML) patients, many face a relapse. This relapse is caused by survival of chemotherapy-resistant leukemia (stem) cells (measurable residual disease; MRD). Here, we demonstrate that the anthracycline doxorubicin epigenetically reprograms leukemia cells by inducing histone 3 lysine 27 (H3K27) and H3K4 tri-methylation. Within a doxorubicin-sensitive leukemia cell population, we identified a subpopulation of reversible anthracycline-tolerant cells (ATCs) with leukemic stem cell (LSC) features lacking doxorubicin-induced H3K27me3 or H3K4me3 upregulation. These ATCs have a distinct transcriptional landscape than the leukemia bulk and could be eradicated by KDM6 inhibition. In primary AML, reprogramming the transcriptional state by targeting KDM6 reduced MRD load and survival of LSCs residing within MRD, and enhanced chemotherapy response in vivo. Our results reveal plasticity of anthracycline resistance in AML cells and highlight the potential of transcriptional reprogramming by epigenetic-based therapeutics to target chemotherapy-resistant AML cells.

Keywords: Cancer; Molecular biology; Therapy.