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A postgraduate research opportunity at the University of Otago.


Academic background
Health Sciences
Host campus
Master's, PhD, Honours
Pathology (Dunedin)
Professor Julia Horsfield, Dr Jisha Antony


Acute myeloid leukaemia (AML) is an aggressive cancer of the bone marrow with an overall survival of ~30%. Outcomes for older patients are especially poor, with cure rates of only 10-15%. Treatment for AML has not changed substantially in more than 30 years and new therapies are urgently needed.

The cohesin complex plays key roles in the three-dimensional (3D) organisation of chromatin and is essential for cell division and gene expression.
Mutations in cohesin are found in 12-15% of AMLs and promote leukaemia by blocking cell differentiation and promoting self-renewal.

Cohesin brings regulatory elements, known as 'enhancers', to genes, to regulate their expression in response to signalling pathways. Our group found that cohesin mutations lead to dysregulated expression of the RUNX1 and ERG genes, which are crucial for haematopoiesis and are frequently altered in AML.

Chromosomal translocations also contribute to AML and include the t(8;21) translocation. Cohesin mutations significantly co-occur with t(8;21), and with other alterations to the RUNX1 gene. Abnormal Wnt signalling is found in AML, and Wnt stimulation increases transcription of both RUNX1 and its t(8;21) translocation partner, RUNX1T1.

The overall aim of this project is to determine if aberrant Wnt signalling and cohesin mutations converge to increase the frequency of the AML translocation: t(8;21)(q22;q22.1); RUNX1-RUNX1T1.

Fluorescence in situ hybridisation (FISH) to determine if cohesin mutations enhance contact between RUNX1 and RUNX1T1 following Wnt stimulation. Stimulation of the Wnt pathway leads to RUNX1T1 being brought into spatial proximity with RUNX1 in human hematopoietic cells. FISH will be used to measure frequency of the spatial coincidence of RUNX1T1 with RUNX1 upon Wnt induction in cohesin-mutant vs wild type leukemia cells.

Determine if Wnt signalling drives cohesin recruitment to RUNX1. The RUNX1 gene contains binding sites for Wnt effectors at its strong intronic +24 enhancer, and at the P1 and P2 promoters. We hypothesise that Wnt signalling drives recruitment of cohesin to these sites at RUNX1. Cohesin-mutant and wild type leukemia lines will be stimulated with Wnt3A or Wnt agonists. 'Cut & Run' using antibodies detecting RAD21 will be used to determine if stimulation promotes cohesin binding to RUNX1. The results will show if RUNX1 is directly targeted by Wnt in leukemia cells.

The results of this project would provide convincing evidence that Wnt signalling causes cohesin to bind to the RUNX1 leukemia gene, and show for the first time that cohesin mutation facilitates the previously observed Wnt-stimulated t(8;21) translocation.


Julia Horsfield

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