Leukaemia: studying the cancer cells that get away

National Stem Cell Foundation of Australia

Heather Lee is analysing individual cancer cells to understand how some survive therapy. Her research ultimately aims to prevent relapse and lift survival rates for leukaemia.

Heather invented a way to study the genetics of individual cells more closely that will help her find out why some cancer cells are treatable, and others go rogue. With her new technique, she can see the chemical ‘flags’ that tell the cell how to interpret its genetic code. At the same time, she can watch how those instructions are—or aren’t—carried out. 

Heather and other scientists use the technique to study what makes rogue cancer cells different at a genetic level.

Heather is now studying cells from patients with acute myeloid leukaemia (AML) to see how just a few cells can resist treatment and go on to cause a fatal relapse. She hopes this will lead to new, more effective drug treatments for this devastating disease.

Dr Heather Lee is a Cancer Institute NSW Fellow at Hunter Medical Research Institute and the University of Newcastle.

In recognition of her leadership in stem cell research, Heather Lee has received one of two $50,000 Metcalf Prizes from the National Stem Cell Foundation of Australia.

Each of us starts life as a single stem cell with our own unique genetic blueprint—our genome. And every cell in your body today contains that same encyclopedia-like blueprint.

Heather is interested in the intricacies of how that one set of instructions is used to produce the hundreds of different types of cells in the body. It can involve molecules that act as gene switches, and chemical flags that tell the cell which parts of the genome to read and which to ignore.

Heather started exploring stem cells and genetics during her PhD at UNSW. She studied how stem cells drive breast growth during pregnancy to allow lactation after birth. She found that this process involves rearrangement of the chemical flags that serve as markers on DNA, highlighting the relevant sections of the genetic code.

“These flags, which we call DNA methylation, don’t alter the sequence of the genetic code, but they change how it’s used. It’s really important in specifying different types of cells with different jobs to do. As stem cells moves towards a specialised function they have to acquire these chemical flags to keep doing that specialised function properly.”

Heather went on to study embryonic stem cells at Cambridge in the United Kingdom.

“Embryonic stem cells are the earliest stem cells. They have the ability to become any cell in the body, but they are not uniform,” Heather says.

“They differ from each other quite a lot, in terms of which genes are expressed, which parts of the genetic code are being read. My research focused on these chemical flags and how they contribute to the differences between embryonic stem cells.”

Changing the game-changer

Heather has pioneered a new technique for single-cell sequencing. Previously, sequencing experiments, used to study our genetic material, needed tissue samples of multiple cells for analysis. This meant rare cells couldn’t be studied, and that variations between cells in a sample might go unnoticed.

Single-cell sequencing was a game-changing technique, allowing the genetics of rare and individual cells to be studied in unprecedented detail. While at Cambridge, Heather took single-cell sequencing a step further, developing a new technique to sequence both a single cell’s DNA methylation across its entire genome and its gene expression. This information can reveal genetic mutations and their effects. It’s particularly important in cancer research.

Catching the cancer cells that get away

Heather says it’s vitally important to analyse the different types of cells present in a tumour individually because the different cells may respond to treatment in different ways.

“There’s quite a bit of evidence to suggest that rare cells that can survive therapy will then cause cancer to regrow,” Heather says.

Certain cancers, like breast cancer and some leukaemias, are known to be driven by cancer stem cell populations. A treatment can appear to have completely wiped out the cancer, but if even a few stem cells survive the cancer can come back.

“Most people diagnosed with breast cancer have good prospects. There are pretty good options for treatment,” Heather says. “But if it comes back after a successful treatment first time around, there are fewer treatment options and the outcomes are much worse.”

Heather returned to Australia to apply her sequencing expertise to tackling cancer at Hunter Medical Research Institute. She’s working on single-cell analysis of cells from patients with AML, an aggressive form of leukaemia.

Each year, more than 1,000 Australians are diagnosed with AML. Sadly, the majority of these people will die from their disease within 5 years.

Heather is studying how AML cells respond to the drugs used in treatment, and working with other scientists and haematologists on testing new drug combinations.

“I’ve shown that some of the cells respond to the drugs, while others do not. Now I want to understand why those cells don’t respond. These are drugs have been around for a long time. However, we still don’t know exactly how they work. No one has had the opportunity to look at how individual cells respond to the drug until now.”

Heather says the Metcalf Prize will allow her to collaborate with other scientists and introduce her new sequencing technique to the Australian research community.

“In five years’ time, I’d like to have some leads we can take into clinical trials, whether that be new drug combinations to target resistant cell populations or new ways to screen patients at risk of relapse. I’m really enjoying working in leukaemia now, where I hope my work will eventually benefit patients.”


2011                     Doctor of Philosophy (Medicine), University of New South Wales

2004                     Bachelor of Science (Honours I), University of Sydney

Career Highlights, Awards, Fellowships, Grants

2018–2020       Lee HJ. Single-cell analysis for improved epigenetic therapy in acute myeloid leukaemia. Cancer Institute NSW Early Career Fellowship.

2018–2019        Lee HJ. Targeting cancer-initiating cells with DNA methyltransferase inhibitors: single-cell analysis to decipher molecular mechanisms and improve efficacy. NHMRC New Investigator Project Grant.

2017                     Lee HJ. High Throughput Robotics Platform for Single-cell Epigenomics. Ian Potter Foundation Medical Research Grant.

2017                     Short-listed for the L’Oreal Australia and New Zealand Fellowship for Women in Science (top 8% of applicants).

2014                     Best Postdoc Presentation, Babraham Institute Annual Lab Talks

2006–2009        Australian Postgraduate Award, The University of NSW

2006–2009        Rising Star Postgraduate Award, The University of NSW Faculty of Medicine

2007                     The Harvey Carey Memorial Scholarship for Outstanding Research in Reproductive Endocrinology, The University of NSW Faculty of Medicine

2003                     E.N. Ted O’Reilly Memorial Prize for Excellence in Plant Physiology, The University of Sydney

2001–2003        Member of The Talented Students’ Program, The University of Sydney Faculty of Science

2001, 2002        Dr Ellen Mary Kent Hughes Prize for Excellence in Science, The Women’s College, The University of Sydney

Key Publications

Lee HJ, Gallego-Ortega D, Ledger A, Schramek D, Joshi P, Szwarc M, Cho C, Lydon JP, Khokha R, Penninger JM, Ormandy CJ (2013). Progesterone drives mammary secretory differentiation via RankL-mediated induction of Elf5 in luminal progenitor cells. Development 140:1397-1401.

Lee HJ*, Hore TA*, Reik W (2014). Reprogramming the Methylome: Erasing Memory and Creating Diversity. Cell Stem Cell 14:710-719. (*contributed equally)

Smallwood SA*, Lee HJ*, Angermueller C, Krueger F, Saadeh H, Peat J, Andrews SR, Stegle O, Reik W, Kelsey G (2014). Single-cell genome-wide bisulfite sequencing for assessing epigenetic heterogeneity. Nature Methods 11:817–820. (*contributed equally)

Angermueller C*, Clark SJ*, Lee HJ*, Macaulay IC*, Teng MJ, Hu T, Krueger F, Smallwood SA, Ponting C, Voet T, Kelsey G, Stegle O, Reik W (2016). Parallel single–cell bisulfite and RNA–sequencing link transcriptional and epigenetic heterogeneity. Nature Methods 13:229-232. (*contributed equally)

Rulands S*, Lee HJ*, Clark SJ, Angermueller C, Smallwood SA, Krueger F, Mohammed H, Dean W, Nichols J, Rugg-Gunn P, Kelsey G, Stegle O, Simons BD, Reik W (2018). Genome-scale oscillations in DNA methylation during exit from pluripotency. Cell Systems 7:63-76. (*contributed equally)