9 Sep 2016

Suspect exposed in aggressive blood cancers

Jody Haigh's group. L-R: Dr Katharina Haigh, Mr John Drummond,
Mr Mina Takawy, Dr Catherine Carmichael, A/Prof Jody Haigh,
Dr Maggie Costa. See more about the lab & its research.
by Anne Crawford

Monash researchers are progressing work into genes which they have revealed initiate aggressive forms of leukaemia. They hope that the genetic tools they have developed for their investigations will be used to identify novel compounds for the treatment of cancers including Early T-cell precursor leukaemia (ETP-ALL) and other related blood diseases.



Headed by Associate Professor Jody J. Haigh, researchers in the Mammalian Functional Genetics Laboratory at the Australian Centre for Blood Diseases (ACBD)/Monash University’s Central Clinical School (CCS) discovered that sustained expression of the transcription factor ZEB2 is involved in human T-cell leukaemia. Transcription factors are proteins that control the transcription and expression of specific genetic information. The work, published last year, was part of a large international collaboration including close interactions with the group of Professor Frank Speleman and Associate Professor Pieter Van Vlierberghe in Ghent, Belgium.

The team analysed patient material with ETP-ALL, a subtype of T-cell acute lymphoblastic leukaemia (T-ALL) that is resistant to treatment and found evidence for increased expression of ZEB2. Using mouse models they showed that increased Zeb2 expression could drive spontaneous T-ALL. They further found that the IL-7 receptor became increased in its expression as a result of increased ZEB2.

“We could show that by decreasing signalling for this receptor that you could reduce the ability of the cells to give rise to leukaemia when transplanted into mice,” Associate Professor Haigh said.

“By understanding what genes ZEB2 is controlling, as well as who it’s interacting with, we might be able to gain novel therapeutic insights into treating the diseases it causes.”

Associate Professor Haigh hopes that pre-clinical trials into ETP-ALL will follow and that research will be broadened to include other diseases such as acute myeloid leukaemia (AML).

He has been investigating ZEB2 and haemopoiesis (the production of blood cell components) since 2011 and was part of a group based at the VIB (Vlaams Instituut voor Biotechnologie) and Ghent University in Belgium that was the first to show that ZEB2 played an important role in blood cell development.

Associate Professor Haigh joined the ACBD in August 2013, moving to the Alfred site with his research group. The team has since collaborated on a number of papers on ZEB2 pointing to its importance as a transcription factor in regulating the development of immune cells.

“Over the past few years we’ve discovered that ZEB2 is an important modulator for many different haemopoetic cells and that when you start altering ZEB2 levels you can really mess up their normal differentiation and function,” Associate Professor Haigh said.

“If you have no ZEB2 in those specific cell types you don’t have properly functioning T cells, Natural Killer cells or dendritic cells,” he said. “These findings raise the interesting question of how to specifically interfere with Zeb2 function in cancer without affecting its role in immune cell function, which is important in controlling cancer growth and spread.”

What was once a niche area has now become a popular focus, with the ACBD team contributing not only knowledge to the growing field but also valuable tools, such as transgenic mice that allow scientists to look at the consequences of overexpression of ZEB2 in a cell-specific way in the context of the whole animal.

The team is now investigating several exciting lines of inquiry flowing from their earlier work, including probing the role of other transcription factors such as the Zeb2 family member Zeb1 as well as the Snai family members.

“These transcription factors have previously been demonstrated to control the ability of solid tumours to spread throughout the body and in regulation of cancer stem cells that give rise to new rounds of tumour growth,” Associate Professor Haigh said.

“Our work will hopefully provide novel insights into these important transcription factors in not only blood cancer but as well in solid tumor spread throughout the body as well as the ability of tumour cells to become resistant to chemo and radiation therapy.”

Mammalian Functional Genetics Laboratory’s work is funded by the NHMRC.

References


Goossens S, Radaelli E, Blanchet O, Durinck K, Van der Meulen J, Peirs S, Taghon T, Tremblay CS, Costa M, Farhang Ghahremani M, De Medts J, Bartunkova S, Haigh K, Schwab C, Farla N, Pieters T, Matthijssens F, Van Roy N, Best JA, Deswarte K, Bogaert P, Carmichael C, Rickard A, Suryani S, Bracken LS, Alserihi R, Canté-Barrett K, Haenebalcke L, Clappier E, RonThedou P, Slowicka K, Huylebroeck D, Goldrath AW, Janzen V, McCormack MP, Lock RB, Curtis DJ, Harrison C, Berx G, Speleman F, Meijerink JP, Soulier J, Van Vlierberghe P, Haigh JJ. ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling. Nature Communications. 2015 Jan 7;6:5794. doi: 10.1038/ncomms6794.

Omilusik, K.D., Best, J.A., Yu, B., Nguyen, J.V., Goossens, S., Seuntjens, E., Weidemann, A., Zweier, C., Bird, L., Kondoh, H., Huylebroeck, D., Haigh, J.J., Goldrath, A.W. A role for transcriptional repressor ZEB2 in the differentiation of CD8+ effector and memory T cell populations. Journal of Experimental Medicine 2015 Nov 16; 212(12):2027-39.

Van Helden*, M., Goossens*, S., Daussy*, C., Debaud, A.L., Faure, F., Marçais, A., Vandamme, N., Mayol, K., Viel, S., Degouve, S., Debien, E., Seuntjens, E., Conidi, A., Chaix, J., Mangeot, P., de Bernard, S., Buffat, L., Haigh, J.J., Lambrecht, B., Huylebroeck, D., Berx, G., and Walzer T. Terminal NK cell maturation I controlled by concerted ctions of T-Bet and Zeb2 and is essential for melanoma rejection.  Journal of Experimental Medicine 2015 Nov 16; 212(12):2015-25.

Charlotte Scott, Bieke Soen, Liesbet Martens, Nicolas Skrypek, Wouter Saelens, Joachim Taminau, Gillian Blancke, Gert Van Isterdael, Danny Huylebroeck, Jody J. Haigh, Yvan Saeys, Martin Guilliams, Bart Lambrecht, and Geert Berx. The transcription factor Zeb2 regulates development of conventional and plasmacytoid DCs. Journal of Experimental Medicine (2016), May 30;213(6):897-911.

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