Research we support

Acute myeloid leukaemia (AML) has low survival rate of 22% in NZ. Treatment options for AML are limited, and new strategies are needed to combat this disease. Cohesin is a protein complex that is important for folding of DNA and regulation of correct gene expression. Mutations in genes of the cohesin complex are present in ~12-20% of AML. AML cells can survive and evade treatment through interaction with the surrounding environment known as the ‘niche’. In previous research we found that cohesin mutation in leukemic cell lines and zebrafish haematopoietic cells, enhances stickiness or adhesive characteristics and this possibly could promote their interaction with the niche and thereby support survival of leukemic cells and disease propagation. 

Zebrafish are excellent models to study leukaemia development in vivo. Our laboratory has well established cohesin mutant zebrafish models. In this project we utilized single-cell gene expression technique to evaluate the blood cell types in the niche of adult cohesin mutant zebrafish. Our results showed that cohesin mutation impairs the composition of blood cell type within the niche and we further identified several genes that are possibly associated with the increased stickiness. The project has evolved into ongoing Health Research Council funded research in which we are further investigating how cohesin mutant cells colonize the niche and testing drugs that may prevent this colonization. 

Standard chemotherapy is not very accurate in killing cancer cells and can damage healthy cells. In
contrast, antibody-drug conjugates (ADCs) act like “guided missiles” that deliver chemotherapy
specifically to cancer cells. ADCs search for targets on the surface of cancer cells and aims to hit
them while leaving healthy cells unharmed. We tested an ADC that looked for a target called
mesothelin (MSLN) on the surface of acute myeloid leukaemia (AML) cells.

We developed a new mouse leukaemia model with the MSLN target to test this medicine. The new
guided missile ADC targeting MSLN was more effective and better tolerated than chemotherapy, but
an unguided missile ADC was just as good.

Our findings suggest the missile's “guidance system” isn’t working. We believe the ADC worked in
other tests, possibly because their MSLN target was too easy to find. Our work added value because
our model was closer to human AML and showed this medicine may not work in patients.

Cyclophosphamide has been in clinical use for more than 60 years, recently it has begun to be used as an immunosuppressive strategy to prevent graft-versus-host disease (GvHD) in allogeneic stem cell transplants. This is typically thought to be because stem cells contain high amounts of an enzyme called ALDH which protects them from the cytotoxic effects of the drug allowing selective deletion of the T-cells (a type of white blood cell) which drives GvHD. Our research project allowed us to demonstrate that there is an additional step in the activation of cyclophosphamide inside human white blood cells and this was tentatively identified as a phosphodiesterase enzyme. Our research suggests that the mechanisms underpinning the selective immunomodulatory effect of this drug may be more complex than previously thought.

Myeloproliferative neoplasms are blood cancers in which the bone marrow makes too many blood cells. One cause of MPN is mutation in a gene called calreticululin. In this project we studied how mutations in this gene changes normal cell stress responses. By understanding these early disease mechanisms, we hope in the future to identify new ways to better target abnormal cell behaviour and ultimately improve treatments for patients.

This research is part of a recently published paper:
CALR Type 1-Like Mutations Increase Endoplasmic Reticulum Free Ca(2+) and Induce ERK1/2 Activation Independent of Thrombopoietin Receptor Activation
M. Faiz, C. Dunstan-Harrison and E. C. Ledgerwood
Cell Biol Int 2025 Vol. 49 Issue 10 Pages 1262-1273

This research project focused on characterising the CAR T-cells used in the ENABLE clinical trials, run by the Malaghan Institute. The trials, which aim to make this type of world-leading cancer therapy accessible to New Zealanders, used a new type of CAR T-cell called ‘1928T2z’. These CAR T-cells are unique compared to other commercially available products, as they include an additional immune activation signal, called toll-like receptor 2 (TLR2). We hypothesised that adding this component into the CAR T-cells would improve their function and safety.