23 Nov 2016

Mutation find may help leukaemia patients

Dr Cedric Tremblay (right) with a co-author,
PhD student Dr Sung Kai Chui.  The
research group has identified a cancer
promoting mutation. See paper.
by Anne Crawford

Researchers from Monash University’s Australian Centre for Blood Diseases (ACBD) have become the first scientists to describe the mechanisms by which a recently identified mutation makes leukaemia cells more aggressive. Their work is progressing in preclinical trials that may lead to the development of a drug to help treat patients with T-cell acute lymphoblastic leukaemia (T-ALL) who are resistant to conventional chemotherapy.

The researchers decided to investigate mutations in the DYNAMIN2 (DNM2) gene after it was first described in paediatric cases of T-ALL in 2012. DYNAMIN 2 is a protein involved in endocytosis, a process that brings substances into cells, internalising them following stimulation of the cells by the environment. DNM2 mutations were frequently detected in T-ALL but the mechanisms linking them to the development of the disease were unknown.

The scientists used a compound of mouse models – the first a mouse carrying the DNM2 mutation, the second one expressing an oncogene promoting T-ALL – to establish that the mutation significantly affected leukaemia development, causing it to arise faster. They performed the experiment in human cells and found that the defective gene was affecting the endocytosis, which brings growth factors into leukaemic cells.

The investigators then observed an increased accumulation of the receptor for the growth factor Interleukin-7 (IL-7): IL-7 was causing the expansion of leukaemia-propagating cells.

“We’d been curious because the DYNAMIN gene is known to be involved in the internalisation of receptors but not in any other functions that could be important for leukaemia,” first author Dr Cedric Tremblay said.

“The mutation was indirectly affecting signalling and allowing cancer cells to survive more and expand so they become more aggressive,” Dr Tremblay said. “We were the first team to describe this.”

The study was conducted in collaboration with scientists elsewhere in Australia and in Spain.

Dr Tremblay said it was part of a broader approach by the ABCD to understand how mutations affect the function of normal blood cells and to target relevant signallings to kill leukaemic cells. He presented the findings – and those of follow-up research – at venues including in Mexico City and San Diego, receiving a Central Clinical School (CCS) grant to travel there.

A $100,000 grant-in-aid from the Leukaemia Foundation of Australia has helped progress the work led by ACBD scientific director Associate Professor David Curtis, and support from CCS head Professor Stephen Jane has also been important, Dr Tremblay said.

The researchers are now working with collaborators in Sydney in preclinical trials to test a proof of concept drug, which has been patented. They hope a new drug will then be developed to ultimately treat patients with T-ALL who are resistant to conventional chemotherapy.

Reference

Tremblay CS, Brown FC, Collett M, Saw J, Chiu SK, Sonderegger SE, Lucas SE, Alserihi R, Chau N, Toribio ML, McCormack MP, Chircop M, Robinson PJ, Jane SM, Curtis DJ. Loss-of-function mutations of Dynamin 2 promote T-ALL by enhancing IL-7 signalling. Leukemia. 2016 Oct;30(10):1993-2001. doi: 10.1038/leu.2016.100.

Lab link: www.acbd.monash.org/research/stem-cell.html

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