Feature: Seeking the source of leukaemia

By the time you read this, Dr Matthew McCormack will likely be surrounded by taped up boxes in his brand new office at the Walter and Eliza Hall Institute (WEHI) in Melbourne. On the brink of that most awful of jobs – moving – McCormack was only too happy to down tools for a moment to talk to ALS about his research since last year’s landmark discovery of the cells responsible for causing a common childhood leukaemia.

Blood cancer remains one of the most common causes of cancer deaths in Australia, despite extensive research over many years and several potentially life-saving discoveries. McCormack’s research focuses specifically on childhood leukaemia, particularly those blood cells that change to become T cell acute lymphoblastic leukaemia (T-ALL), a common cancer in Australian children with about 50 cases diagnosed each year.

The disease also occurs in adults and sadly, about 20 per cent of children and the majority of adult patients eventually succumb due to resistance to treatment or relapse. McCormack essentially wants to find out why this disease is so stubborn and what is treatment strategy might prevent it from coming back.

In early 2010, McCormack and his clinical colleague, Associate Professor David Curtis, published an exciting discovery about T-ALL in Science. McCormack and Curtis were able to identify and isolate a population of self-renewing cells in the thymus of mice prone to developing a very similar leukaemia, which turned out to be the cell of origin for both the development of T-ALL and a possible source of its recurrence after therapy. They did this work in the Bone Marrow Research Laboratories at the Royal Melbourne Hospital, where McCormack worked for seven years prior to his recent move down the road.

“I brought these transgenic mouse models of T-ALL back with me some years ago from my postdoc with Terry Rabbitts’ group in Cambridge at the MRC Laboratory of Molecular Biology,” says McCormack.

“They were developed in Terry’s lab and are a pretty faithful model of human T cell leukaemia. They are 100 per cent penetrant, meaning all animals eventually develop the disease, and the leukaemia appears with an average latency of 10 months. The origins of T-ALL had always been fairly obscure, and we were trying to clarify that using these mice.”

Overexpression of selected oncogenes during T cell development in the thymus is a common cause of paediatric T-ALL. The transgenic mice from Cambridge were genetically engineered to overexpress the transcription factor Lmo2, one of the T-ALL-associated oncogenes.

McCormack and the team in Melbourne used a clever fluorescent cell-fate tracking strategy, which distinguishes cells derived from the bone marrow (home of the blood stem cell) from those in the thymus itself, and discovered a cell population within the thymus of the Lmo2-transgenic mice that could persist independently of the bone marrow and that appeared at least eight months before the development of leukaemia.

Not only were these cells present in the thymus essentially from birth and long before the disease appeared, they also appeared to have stem cell-like properties, says McCormack. This was an extremely exciting find from their point of view.

“These cells divide and self-renew, and they can also differentiate and give rise to mature T cells.” A normal thymus has no self-renewal potential and must be continually replenished by progenitors from the bone marrow for T cell production. Based on such properties, McCormack and Curtis named their newly found thymic cell population as precancerous stem cells (pre-CSCs).

“We coined that term to distinguish these cells from cancer stem cells, which describes progenitor cells from overt cancers that can be transplanted into mice and give rise to a tumour straight away.

“The pre-CSCs cells behave similarly in that they can be transplanted into irradiated recipient mice and engraft long term and they can be serially transplanted. However, they don’t actually give rise to cancer for a relatively long time. We think that human T-ALL patients might have a similar thymus-based stem-cell-like population.”

In further studies, the team found that irradiation treatment of the Lmo2-mice killed over 99 per cent of cells in the thymus, but a small percentage survived and rapidly recovered. Analysis by the cell-lineage assay showed this recovery derived from residual pre-CSCs. “This suggested to us that these cells could survive conventional therapy and be responsible for relapsed disease following treatment.”