Key terms: Hematopoiesis, Acute myeloid leukaemia, T-cell acute lymphoblastic leukaemia, Stem cell self-renewal
2016 McCormack group. L-R: Dr Ben Shields, A/Prof Matthew McCormack, Mr Jacob Jackson.
Our research centers on understanding the roles of transcription factors in normal and leukaemic hematopoiesis. We study how transcription factors alter cellular self-renewal programmes and epigenetic regulatory pathways to promote self-renewal of committed progenitors.
We have shown that a common T-cell oncogene, Lmo2, causes self-renewal of committed T-cells in the thymus. This gives rise to long-term self-renewing stem cells that eventually cause acute T-cell leukaemia (T-ALL). Lmo2 activates a number of genes that are normally expressed in Hematopoietic Stem Cells (HSCs), implying that it uses an HSC-like transcriptional programme. We are currently studying the pathways activated by Lmo2 and other transcription factors in T-ALL. In addition, we are examining the role of these networks in self-renewal of hematopoietic stem cells.
Our second focus is to understand the role of homeobox genes, in particular the Haematopoietically-expressed homeobox gene (Hhex) in blood development an leukemia. We have shown that Hhex is critical for lymphoid development and also for acute myeloid leukemia (AML), where it functions to promote the epigenetic silencing of key tumour suppressor pathways.
Projects and opportunities
- Project title: Studying commonality between T-cell oncogenes
Project description: This project seeks to identify the transcriptional programmes controlled by T-cell oncogenes and compare them at a molecular level. The hypothesis is that several T-cell oncogenes converge on common molecular pathways to drive self-renewal. The identification of critical targets may identify new therapeutic targets.
- Project title: Collaborating oncogenes in T-cell leukemia
Project description: T-cell leukemia involves concurrent dysregulation of a number of pathways including transcription factors, epigenetic modifiers and growth factors. However, how these pathways interact to promote leukemia and affect therapeutic sensitivity of cancer stem cells is presently unclear. This project will investigate this problem using in vitro and in vivo models, flow cytometry and imaging techniques.
- Project title: Role of the Hhex transcription factor in hematopoiesis and leukaemia
Project description: We have shown that T-cell oncogenic transcription factors such as Lmo2 cause overexpression of a number of stem cell genes in T cells. Amongst these is Hhex, a homeobox transcription factor that plays key roles in the development of normal blood stem cells. This project will study the function of Hhex in the self-renewal of Lmo2-induced T-cell leukaemia stem cells and normal blood development, using in vivo models, tissue culture, retroviral gene expression and transcriptome/pathway analysis.
For all current ACBD project opportunity descriptions please visit our Honours page
- 2016-18: McCormack MP, Majewski IJ. NHMRC project grant 1104145. Understanding the multi-step pathogenesis of T-cell leukaemia.
- 2015-17: McCormack MP. NHMRC project grant 1085765. The role of the homeobox transcription factor Hhex in haematopoiesis and leukaemia.
- Shields BJ, Jackson JT, Metcalf D, Shi W, Huang Q, Garnham AL, Glaser SP, Beck D, Pimanda JE, Bogue CW, Smyth GK, Alexander WS and McCormack MP. Acute myeloid leukemia requires Hhex to enable PRC2-mediated epigenetic repression of Cdkn2a. Genes and Development 30(1):78-91, 2016.
- Jackson JT, Nasa C, Shi W, Huntington ND, Bogue CW, Alexander WS, and McCormack MP. A crucial role for the homeodomain transcription factor Hhex in lymphopoiesis. Blood 25(5):803-14, 2015.
- Shields BJ, Alserihi R, Nasa C, Bogue CW, Alexander WS, McCormack MP. Hhex regulates Kit to promote radioresistance of self-renewing thymocytes in Lmo2-transgenic mice. Leukemia 29(4):927-38, 2015.
- McCormack MP, Shields BJ, Jackson JT, Nasa C, Shi W, Slater NJ, Tremblay CS, Rabbitts TH, Curtis DJ. Requirement for Lyl1 in a model of Lmo2-driven early T-cell precursor ALL. Blood 122(12):2093-103, 2013.
- Curtis DJ and McCormack MP. The Molecular Basis of Lmo2-Induced T-Cell Acute Lymphoblastic Leukemia. Clinical Cancer Research 16(23):5618-23, 2010
- 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 327(5967):879-83, 2010