Acute myeloid leukemia (AML) is a disease characterized by the disruption of gene expression (transcriptional dysregulation), resulting in a block in cellular differentiation and aberrant self-renewal. The majority of AML patients achieve an initial deep response in the first phase of treatment with chemotherapy, consisting of cytarabine and an anthracycline such as doxoxrubicin. However, a small population of leukemia cells survives the induction therapy, called measurable residual disease (MRD).

MRD is the origin of relapse, which is the major cause of the very poor five-year survival rate of AML patients. Currently, there are no effective treatment options available that eliminate this small population of residual disease.

The team of Dr. Linda Smit at the department of Hematology and collaborators are developing novel treatment strategies targeting MRD. They have now discovered that doxorubicin induces the methylation of histone 3 lysine 27 (H3K27) in cells sensitive to the drug. However, this methylation does not occur in cells resistant to the treatment: the ‘persisters’.

Moreover, the doxorubicin-resistant cells have a dynamic phenotype with a distinct transcriptional profile from other leukemia cells. The team found that these persisters could be eradicated by inhibition of the histone demethylase KDM6. The inhibition of KDM6 also reduced MRD load and survival of leukemic stem cells residing within MRD.

The study reveals plasticity of resistance in AML cells and highlights the potential of transcriptional reprogramming by epigenetic based therapeutics to target chemotherapy-resistant AML cells. This research was published in the journal ‘iScience’.

For more information contact Dr. Linda Smit, or read the publication: Van Gils, N., et al. (2022) Targeting histone methylation to reprogram the transcriptional state that drives survival of drug-tolerant myeloid leukemia persisters. iScience 25, 105013. https://doi.org/10.1016/j.isci.2022.105013

Researchers involved at Cancer Center Amsterdam – Amsterdam UMC:

Noortje van Gils

Han Verhagen

Tania Martiáñez

Fedor Denkers

Eline Vermue

Arjo Rutten

Tamás Csikós

Meryem Cil

Marjon Al

Jeroen Janssen

Gert Ossenkoppele

Renee Menezes

Linda Smit

Funding for this study was provided by the Dutch Cancer Society (KWF) and the Foundation ‘De Drie Lichten’.