Modelling the multi-step pathogenesis of T-cell leukaemia

Project type

Honours

Supervisor(s)	Division	Email
Dr Matthew McCormack (Primary)	Cancer and Haematology	.(JavaScript must be enabled to view this email address)
Professor Warren Alexander (Co-supervisor)	Cancer and Haematology	.(JavaScript must be enabled to view this email address)

Details of project

We are studying mouse models of T cell acute lymphoblastic leukaemia (T-ALL), a common paediatric leukaemia. T-ALL is commonly caused by overexpression of transcription factors during normal T cell development. We have recently shown that one such transcription factor, Lmo2, gives immature T cells the stem cell-like property of self-renewal. This leads to a protracted preleukaemic state in which preleukaemic stem cells (pre-CSCs) self-renew in the thymus allowing secondary mutations to occur which culminate in leukaemia (Figure 1).

However, less is known about these secondary mutations and their effects on pre-CSCs. This project will use in vitro and in vivo models to study the effects of common secondary mutations on pre-CSCs directly. This will involve tissue culture, gene expression analyses and transplantation studies using mice. In addition, we will use a combination of array-based and screening approaches to identify novel secondary mutations and characterise their effects on pre-CSCs. This will enhance our understanding of the multi-step process leading to T-ALL and may uncover new therapeutic approaches.

<p>Figure 1. Precancerous stem cells (pre-CSCs) arise through the activation of transcription factors such as Lmo2 in developing T-cell progenitors in the thymus. This project will characterise the additional mutations that convert pre-CSCs into cancer stem cells (CSCs) that cause overt leukaemia
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Project references

Curtis DJ, McCormack MP. The molecular basis of Lmo2-induced T-cell acute lymphoblastic leukemia. Clin Cancer Res. 2010 Dec 1;16(23):5618-23. PMID: 20861166
McCormack MP, Young LF, Vasudevan S, de Graaf CA, Codrington R, Rabbitts TH, Jane SM, Curtis DJ. The Lmo2 oncogene initiates leukemia in mice by inducing thymocyte self-renewal. Science. 2010 Feb 12;327(5967):879-83. PMID: 20093438

Research interests

Stem cells replenish our tissues throughout life. To achieve this, they have the property of self-renewal, in which stem cells divide without maturing. However, cancer-causing mutations can give self-renewal abilities to cells that have normally lost this property. These cells then persist long-term as “precancerous stem cells” whilst acquiring additional mutations that lead to overt cancer. Precancerous stem cells are intrinsically resistant to conventional cancer therapy, implying that they may be a source of disease relapse.

Our laboratory studies precancerous stem cells that cause T cell leukaemia. We aim to discover the self-renewal pathways that are induced by cancer-causing genes that give self-renewal properties to developing T cells in the thymus. We also study the role of these genes in normal blood stem cell function.

In addition, we are investigating therapeutic strategies to target precancerous stem cells in T cell leukaemia.

Selected publications

1. Aifantis I, Raetz E, Buonamici S. Molecular pathogenesis of T-cell leukaemia and lymphoma. Nat Rev Immunol. 2010 8(5):380-390. PMID: 18421304

Research theme

Cancer

Scientific discipline

Haematology

Keywords

Leukaemia, T-cells, self-renewal, stem cells

The Walter and Eliza Hall Institute of Medical Research