Fishing for answers: acute myeloid leukaemia

9 June 2017

Professor Anskar Leung uses zebrafish to study one of the most fatal cancer in the world, acute myeloid leukaemia, a form of blood cancer in which immature white blood cells are overproduced in the bone marrow.

Professor Anskar Leung (Croucher Senior Medical Research Fellow 2017) is a haematologist and Clinical Professor in the Department of Medicine at the University of Hong Kong, with Acute Myeloid Leukaemia as his research focus. Leung’s study of the disease using zebrafish has provided drug-screening platform for its treatment, which in turn can help scientists achieve personalised treatment of blood cancers.

AML is a rare but one of the most fatal cancers worldwide. It is a form of blood cancer characterised by overproduction of immature white blood cells in the bone marrow, which interferes with the normal marrow functions. The risk of AML increases with age and can progress rapidly if not treated.

Personalised treatment of blood cancers

Leukaemia is a heterogeneous disease with multiple types and subtypes, with different pathogenesis even within AML. But the current treatment is uniform with chemotherapy and bone marrow transplantation. More than half of the patients don’t survive.

“Majority of patients die either due to refractory diseases or can’t withstand repeated chemotherapy and die of organ failure,” said Leung. “We want to see if pre-testing drug sensitivity in the laboratory will help us to define better treatment in the clinics.”

With that in mind, Leung’s team collected blood and marrow samples of 100 leukaemia patients, performed genetic tests and evaluated their sensitivity to 25 clinical drugs, whose specific effects on AML subtypes are largely unknown. He found that homoharringtonine, a herbal extract, is very effective in the treatment of an AML subtype that carries a gene mutation known as FLT3. At present, patients with this gene mutation may respond transiently to chemotherapy but most of them would relapse and become refractory.

Thereafter, Leung’s team examined in details the therapeutic mechanisms of homoharringtonine with particular reference to FLT3 mutant AML and its potential synergism with FLT3 inhibitors whose clinical efficacy has been very transient and undesirable. Using xenotransplantation model in which human leukaemia cells were transplanted into immunodeficient mice, homorringtonine treatment was also shown to be effective in reducing leukaemia cell burden and prolonged the lifespan of the leukaemic mice.

The next step was a clinical trial, where combination treatment was tested on AML patients with FLT3 mutation and it was found to be effective, to an extent that this is now a standard of care in Hong Kong for patients with AML subtype with FLT3 mutation.

Leung and his team’s research on different subtypes of AML and subsequent platform for drug screening is a work in the direction of achieving personalised treatment of blood cancers.

“While this discovery was quite interesting, it only solves a small fraction of problem, given FLT3 mutation occurs in only 20 percent of the leukemic patients. There are many other types of leukaemia for which we don’t have marker to test drug effectiveness,” said Leung.

“The main priority is to improve cell culture platform and the drug library,” he added. Since the team started their experiment four years ago, several new drugs have been introduced to the market, and are proven to be effective for cancers of solid organs. Leung plans to incorporate new drugs in the library, and see if the new drugs are also effective for blood cancers. The team is currently undertaking an experiment with larger number of samples with a goal of finding another subtype of leukaemia sensitive to a different drug.

“Given how heterogeneous leukaemia is, we hope that our research will become a model for other people to adopt and see whether one can tailor-make ideal regimen for individual patients by pre-testing them in the laboratory,” added Leung.

Research into Haematopoiesis

Haematopoiesis is a process by which blood is formed in the body. Certain genes are known to be involved in causing Leukaemia and at the same time, are also essential for the normal formation of blood cells. Leung’s research also involves investigating whether leukemic genes are involved in the process of blood formation.

A lot of investigation used mouse as animal model but it took a lot of effort and time to generate mutant mouse with the same features as that of human leukaemia.

“We tried to overcome this problem by using zebrafish model. By knocking in specific gene mutations in the zebrafish and creating zebrafish lines that carry the mutation, we want to see if the gene mutations are causing leukaemia on their own or in combination with other genes,” he explained. ”If we have such model then we can use the whole organism as a drug screening platform.”

Zebrafish has an edge over the mouse as a model system because the development of the small tropical freshwater is very fast, making it cost effective for science experiment. Additionally, zebrafish is optically transparent with external fertilisation, unlike in case of mouse, enabling researchers to see through the fish their development from one stage to another, and of vital body parts like heart, brain, and blood vessels. Most importantly, human and zebrafish embryo share 80 percent of the genes, making it an ideal model organism.

New research direction and challenges

Although research into AML takes pretty much all of his working hours, Leung wants to explore the effectiveness of immunotherapy for acute leukaemia.

Immunotherapy has been shown to be very useful in many solid cancers and lymphoma, but its effectiveness in treating blood cancers is yet to be seen. Immunotherapy involves drugs that unleash one’s own immune system and enhance its ability in killing cancer cells and curing the tumour.

After spending years in both the clinical and translational field of medical science, Leung realises the importance of clinicians and basic scientists working together, and at the same times adds that scientists have to be involved in translational part as well, with foreseeable implication of the work, so as not to lose momentum in their research.

Said Leung: “A closer collaboration between scientists and clinicians is very important, especially in Hong Kong where faculties are much smaller. We need to have better focus and work together if we are to do something great to benefit the humankind.”

Professor Leung obtained his MBChB (Hons) and PhD from the Chinese University of Hong Kong in 1996. In 2000 he received Croucher Fellowship at the University of Minnesota. He received his specialist qualification in Haematology and Haematological Oncology in 2003. He was a recipient of Croucher Senior Medical Research Fellow in 2017.

He jointed the University of Hong Kong as Clinical Assistant Professor in 1999. He was promoted to Clinical Associate Professor and Clinical Professor in 2007 and 2012 respectively. Professor Leung is currently a Clinical Professor in the Department of Medicine at the University of Hong Kong and also the Associate Dean of the Li Ka Shing Faculty of Medicine, HKU. Professor Leung is currently the Honorary Consultant of Queen Mary Hospital.

To view Professor Leung's Croucher profile, please click here.