Finding boosts target hopes for aggressive blood cancers

2016 Mammalian Functional Genetics Laboratory group
L- R: Dr Katharina Haigh, Mr John Drummond, Mr Mina Takawy,
Dr Catherine Carmichael, Assoc Prof Jody Haigh, Dr Maggie Costa,
Absent: Dr Thao Nguyen

by Anne Crawford 

In September last year this blog reported on some promising findings into ZEB2, a protein implicated in certain aggressive leukaemias, made by Australian Centre for Blood Diseases (ACBD) researcher, Associate Professor Jody Haigh as part of an international collaboration.

Associate Professor Haigh’s work has since been bolstered by the revelation of a novel partner of ZEB2. Combined, they may form a possible therapeutic target that could potentially have greater efficacy than targeting ZEB2 alone.

Researchers in the ACBD’s Mammalian Functional Genetics Laboratory previously helped discover a link between the sustained expression of ZEB2 (Zinc finger E-box binding homeobox transcription factor-2) and human T-cell leukaemia. T-cells play important roles in immunity.

Using mouse models they showed that increased Zeb2 expression could drive a subtype of T-cell acute lymphoblastic leukaemia called ETP-ALL, a disease characterised by a high incidence of remission failure after chemotherapy.

In research published in the journal ‘Blood’ in January the scientists identified an epigenetic modifying enzyme called KDM1A/LSD1 as a novel interaction partner of ZEB2. They demonstrated that mouse and human T-ALLs with increased ZEB2 levels critically depend on KDM1A activity for survival.

Targeting the ZEB2-KDM1A interaction or pharmaceutically inhibiting the enzyme itself could serve as a novel therapeutic strategy for this aggressive subtype of human leukaemia and possibly other ZEB2-driven malignancies.

“I think this is the first time it has been shown that KDM1A inhibition can be used with T-ALL, at least in preclinical mouse models,” Associate Professor Haigh said. “We also got some clues on how it might be acting on the cells and how these cells might be developing resistance against this inhibitor,” he said.

“If we could develop synergistic strategies to be used to inhibit certain ZEB2 targets and put together KDM1A inhibitors it might be better for patients as a novel therapeutic tool for the treatment of ZEB2- driven tumors.”

The experiments used leukaemic cells from transgenic mice with the ZEB2 protein overexpressed.
“We put a little tag on ZEB2 – a short amino acid sequence – and used an antibody against this tag so you could pull it down and see the proteins that interacted with it,” Associate Professor Haigh explained. “We then used mass spectrometry analysis to determine who are the interacting proteins.”

Finding KDM1A at the scene was exciting, particularly as inhibitors against KDM1A are currently in Phase 1 clinical trials for another cancer – Acute Myeloid Leukaemia (AML) – as well as other solid tumors. But the researchers were aware that they weren’t the only scientists investigating its role in blood cancers at the time – a group from Harvard University (Professor David Pellman’s lab) had recently found a link between ZEB2 and KDM1A in AML. No functional data concerning the interaction was presented though.

The findings did not directly overlap but the ACBD team were at risk of being scooped to a certain extent.

Associate Professor Haigh contacted the Harvard researchers concerning another paper in which they were involved concerning the role of Zeb2 in myeloid differentiation defects and successfully suggested trying to have the results published in ‘Blood’ together.

“It gave us more validity – these two totally independent groups working in totally different areas across the world to come across the same thing. It was gratifying, it made it ‘real’,” Associate Professor Haigh said.

The ACBD researchers were working in collaborations with Associate Professor Pieter Van Vlieberghe’s group based at Ghent University in Belgium and with Viktor Janzen’s group at Bonn Medical School in Germany. The co-first author on both of these studies was Dr Steven Goossens, who was based at the ACBD for a year and previously worked in the Haigh lab at the VIB/Ghent University in Belgium.

References
Goossens S*, Peirs S*, Van Loocke W, Wang J, Takawy M, Matthijssens F, Sonderegger SE, Haigh K, Nguyen T, Vandamme N, Costa M, Carmichael C, Van Nieuwerburgh F, Deforce D, Kleifeld O, Curtis DJ, Berx G, Van Vlierberghe P, Haigh JJ. Oncogenic ZEB2 activation drives sensitivity towards KDM1A inhibition in T-cell acute lymphoblastic leukemia. Blood. 2017 Jan 9. pii: blood-2016-06-721191. doi: 10.1182/blood-2016-06-721191. [Epub ahead of print]

Jin Li*, Tamara Riedt*, Steven Goossens*, Carmen Carrillo García, Sabrina Szczepanski, Maria Brandes, Tim Pieters, Linne Dobrosch, Ines Gütgemann, Natalie Farla, Enrico Radaelli, Paco Hulpiau, Nikhil Mallela, Holger Fröhlich, Roberta La Starza, Caterina Matteucci, Tong Chen, Peter Brossart, Cristina Mecucci, Danny Huylebroeck, Jody J. Haigh and Viktor Janzen.  The EMT transcription factor Zeb2 controls adult murine hematopoietic differentiation by regulating cytokine signalling. Blood 2017 129:460-472; doi: 10.1182/blood-2016-05-714659.

Sara E. Meyer.  From EMT to HSC to AML: ZEB2 is a cell fate switch.  Blood 2017 129:400-401; doi: 10.1182/blood-2016-11-748186