A new study from UHN’s Princess Margaret Cancer Centre (PM) found that ancient DNA sequences in our genome, called transposable elements, can act as control hubs for leukemia stem cells, fueling therapy resistance and relapse in acute myeloid leukemia (AML). Although most patients with AML achieve complete remission after chemotherapy, two-thirds will relapse within five years.

Lifelong blood production originates from self-renewing, hematopoietic stem cells (HSCs)—cells that give rise to different types of immature (precursor) and mature blood cells. In blood cancers such as leukemia, cancer stem cells can self-renew and give rise to cancerous cells.

A small group of powerful cancer stem cells, called leukemia stem cells (LSCs), is one of the biggest obstacles to curing blood cancers. LSCs can survive chemotherapy, reignite the disease, and drive relapse. However, the genetic reasons why LSCs remain so resilient are poorly understood.

By comparing how DNA is packaged and accessed (a process known as epigenetics) in LSCs, HSCs, and more mature blood cells, researchers found that transposable elements—sometimes called "jumping genes" because they can move around the genome—help distinguish stem cells from more mature, specialized blood cells.

The team, including first authors Drs. Giacomo Grillo and Bettina Nadorp, found that specific families of transposable elements, such as ERV1 and ERV3, are highly active in LSCs. These same elements normally function in healthy blood stem cells to support self-renewal.

Transposable elements are an under-explored class of DNA sequences, making up roughly 50% of the human genome. “They are not genes, but they can turn on genetic programs that allow cells to renew and thrive. In this way, leukemia stem cells hijack what healthy blood stem cells use for regeneration, fueling cancer relapse instead,” says Dr. Mathieu Lupien, Senior Scientist at PM and co-senior author of the study.

Building on this discovery, the researchers developed a genomic score that can identify patients with AML who are more likely to relapse. The score measures how closely a patient's leukemia cells resemble LSCs by examining whether specific families of transposable elements are found in open, accessible regions of the genome.

Through efforts led by Dr. John Dick, Senior Scientist at PM, and his team, including Senior Scientific Associate Dr. Helena Boutzen, chemical tools were used to selectively mask and disable certain transposable elements in preclinical models of leukemia. Doing so resulted in LSCs losing their ability to renew and thrive, opening the door to new possible therapeutic strategies.

 “Together, these findings give us hope that we can eliminate leukemia at its root and not just decrease the burden of the disease,” says Dr. Lupien. “We may finally change outcomes for patients living with AML.”

Dr. Giacomo Grillo, former postdoctoral researcher at UHN and currently a Staff Scientist at the European Institute of Oncology, is a co-first author of the study.

Dr. Bettina Nadorp, former postdoctoral researcher at UHN and currently an Associate Director at Bristol Myers Squibb, is a co-first author of the study.

Dr. Helena Boutzen, Senior Scientific Associate at Princess Margaret Cancer Centre, is a co-author of the study.

Dr. John Dick, Senior Scientist at Princess Margaret Cancer Centre, University Professor at the University of Toronto, Helga and Antonio De Gasperis Chair in Blood Cancer Stem Cell Research, and Professor in the Department of Molecular Genetics at the University of Toronto, is a co-corresponding author of the study.

Dr. Mathieu Lupien, Senior Scientist at Princess Margaret Cancer Centre and Professor in the Department of Medical Biophysics at the University of Toronto, is a co-corresponding author of the study.

This work was supported by The Princess Margaret Cancer Foundation, Ontario Institute for Cancer Research, the Province of Ontario, the Canadian Institutes for Health Research (CIHR), Medicine by Design, The Terry Fox Research Institute, the Canada Research Chairs program, the Canadian Cancer Society Research. Dr. Lupien holds the Joey and Toby Tanenbaum/Brazilian Ball Chair in Prostate Cancer Research at UHN's Princess Margaret Cancer Centre.

Giacomo Grillo, Bettina Nadorp, and Aditi Qamra report that at the time of publication, they were employees of T-One Therapeutics, Bristol Myers Squibb, and Hoffman-La Roche Canada, respectively.

Grillo G, Nadorp B, Qamra A, Drylie B, Mitchell A, Arlidge C, Nand A, Takayama N, Murison A, Madani Tonekaboni SA, Kang KK, Arruda A, Wang JCY, Minden MD, Deniz Ö, Boutzen H, Dick JE, Lupien M. Transposable elements shape stemness in normal and leukemic hematopoiesis. Nat Genet. 2026 May. doi: 10.1038/s41588-026-02585-z. Epub 2026 May 4.