T-ALL can evolve to oncogene independence
- Abdulla, H; Vo, A; Shields, BJ; Davies, TJ; Jackson, JT; Alserihi, R; Viney, EM; Wong, T; Yan, F; Wong, NC; Demoen, L; Curtis, DJ; Alexander, WS; Van Vlierberghe, P; Dickins, RA; McCormack, MP;
- Journal Title
- Publication Type
- epub ahead of print
- 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.
- WEHI Research Division(s)
- Immunology; Blood Cells And Blood Cancer
- PubMed ID
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2021-03-09 08:05:37Last Modified: 2021-03-09 08:22:38