TY - JOUR
T1 - Targeting histone methylation to reprogram the transcriptional state that drives survival of drug-tolerant myeloid leukemia persisters
AU - van Gils, Noortje
AU - Verhagen, Han J. M. P.
AU - Broux, Michael
AU - Martianez, Tania
AU - Denkers, Fedor
AU - Vermue, Eline
AU - Rutten, Arjo
AU - Csikos, Tamas
AU - Demeyer, Sofie
AU - Cil, Meryem
AU - Al, Marjon
AU - Cools, Jan
AU - Janssen, Jeroen J. W. M.
AU - Ossenkoppele, Gert J.
AU - Menezes, Renee X.
AU - Smit, Linda
N1 - Funding Information: This study was supported by grants from the Dutch Cancer Society ( KWF grant no. 12805 ) and the Foundation “ De Drie Lichten ” in the Netherlands (grant no. 52/18 ). Publisher Copyright: © 2022 The Author(s)
PY - 2022/9/16
Y1 - 2022/9/16
N2 - 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.
AB - 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.
KW - Cancer
KW - Molecular biology
KW - Therapy
UR - http://www.scopus.com/inward/record.url?scp=85137288211&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.isci.2022.105013
DO - https://doi.org/10.1016/j.isci.2022.105013
M3 - Article
C2 - 36097617
SN - 2589-0042
VL - 25
SP - 105013
JO - iScience
JF - iScience
IS - 9
M1 - 105013
ER -