T-ALL can evolve to oncogene independence

Hesham Abdulla, Anh Vo, Benjamin J. Shields, Tenae J. Davies, Jacob T. Jackson, Raed Alserihi, Elizabeth M. Viney, Tin Wong, Feng Yan, Nicholas C. Wong, Lisa Demoen, David J. Curtis, Warren S. Alexander, Pieter Van Vlierberghe, Ross A. Dickins, Matthew P. McCormack

Research output: Contribution to journalArticleResearchpeer-review

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 languageEnglish
Number of pages15
JournalLeukemia
DOIs
Publication statusAccepted/In press - 22 Jan 2021

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