Projects per year
Abstract
The majority of cases of T-cell acute lymphoblastic leukemia (T-ALL) contain chromosomal abnormalities that drive overexpression of oncogenic transcription factors. However, whether these initiating oncogenes are required for leukemia maintenance is poorly understood. To address this, we developed a tetracycline-regulated mouse model of T-ALL driven by the oncogenic transcription factor Lmo2. This revealed that whilst thymus-resident pre-Leukemic Stem Cells (pre-LSCs) required continuous Lmo2 expression, the majority of leukemias relapsed despite Lmo2 withdrawal. Relapse was associated with a mature phenotype and frequent mutation or loss of tumor suppressor genes including Ikzf1 (Ikaros), with targeted deletion Ikzf1 being sufficient to transform Lmo2-dependent leukemias to Lmo2-independence. Moreover, we found that the related transcription factor TAL1 was dispensable in several human T-ALL cell lines that contain SIL-TAL1 chromosomal deletions driving its overexpression, indicating that evolution to oncogene independence can also occur in human T-ALL. Together these results indicate an evolution of oncogene addiction in murine and human T-ALL and show that loss of Ikaros is a mechanism that can promote self-renewal of T-ALL lymphoblasts in the absence of an initiating oncogenic transcription factor.
Original language | English |
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Pages (from-to) | 2205–2219 |
Number of pages | 15 |
Journal | Leukemia |
Volume | 35 |
DOIs | |
Publication status | Published - Aug 2021 |
Projects
- 2 Finished
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Understanding the multistep pathogenesis of T-cell leukaemia
McCormack, M. (Primary Chief Investigator (PCI)) & Majewski, I. J. (Chief Investigator (CI))
National Health and Medical Research Council (NHMRC) (Australia)
11/07/16 → 31/12/19
Project: Research
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Therapeutic targeting of precancerous stem cells in T cell leukaemia
Curtis, D. (Primary Chief Investigator (PCI)) & McCormack, M. P. (Partner Investigator (PI))
National Health and Medical Research Council (NHMRC) (Australia)
1/01/11 → 31/12/13
Project: Research