13 Feb 2015

Driver discovered in aggressive form of T-cell acute lymphoblastic leukaemia

Zinc finger E-box binding homeobox 2 protein
Source: Wikipedia ZEB2
The disease Early Thymic Progenitor-cell acute lymphoblastic leukaemia (ETP-ALL) is aggressive, has poor survival rates and doesn't respond well to therapies currently available. Its exact causes have to date not been well understood.

A research group at Monash's Australian Centre for Blood Diseases (ACBD) has identified that increased expression in one transcription factor acts as a driver in the development of ETP-ALL. Dr. Steven Goossens and Associate Professor Jody J. Haigh, who is the leader of the Mammalian Functional Genetics group in the ACBD, have been working on the Zinc finger E-box-binding homeobox 2 (ZEB2) protein.

Associate Professor Haigh said, "The ZEB2 protein usually sits at the bottom of many signalling pathways which regulate cellular contacts, growth and cell renewal.  It's a transcription factor, i.e. it binds to DNA and controls the expression of many genes either in a positive or negative way depending on other co-factors and cell type.

“Normally, ZEB2 is tightly controlled, but if it becomes deregulated it alters the development of T-Cells that then accumulate genetic damage and become the seed of tumour formation. We compared non-ZEB2 with ZEB2 overexpressing T-ALL cells, and it was clear that increased ZEB2 expression leads to a much more aggressive disease.”

The group developed a mouse model that resembles the human disease, and looked at gene expression of the mouse tumours compared with human ETP-ALL samples which could show that a significant number of genes were commonly changed in both the mouse and human diseased cells compared with normal T-Cells.

They found that aggressive T-ALL disease occurred when the ZEB2 protein levels remain high during T-Cell development.

ZEB2 regulates the expression of many genes. One gene in particular makes a type of protein called the IL-7 receptor that binds the IL-7 cytokine, another type of protein which is particularly important in T-cell development. IL-7’s increased activity has been implicated in human disease progression.

"Given the similarities between our mouse models and human ETP-ALL disease we believe that studying this model in greater depth offers promising potential for the development of novel therapeutic compounds that can be used to treat ETP-ALL", said Associate Professor Haigh.
A/Prof Haigh's group has collaborated widely with both local and international expert groups for this research.

Reference: www.nature.com/ncomms/2015/150107/ncomms6794/full/ncomms6794.html
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