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T-ALL can evolve to oncogene independence.

Hesham Abdulla1, Anh Vo2, Benjamin J Shields2

  • 1Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

Leukemia
|January 23, 2021
PubMed
Summary
This summary is machine-generated.

Most T-cell acute lymphoblastic leukemia (T-ALL) cases rely on oncogenes. However, this study shows T-ALL can evolve to independence from these factors, particularly through Ikaros loss, enabling leukemia maintenance.

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Area of Science:

  • Hematology
  • Molecular Biology
  • Oncology

Background:

  • T-cell acute lymphoblastic leukemia (T-ALL) often arises from chromosomal abnormalities leading to oncogenic transcription factor overexpression.
  • The necessity of these initiating oncogenes for sustained leukemia growth remains unclear.

Purpose of the Study:

  • To investigate whether oncogenic transcription factors are essential for maintaining T-ALL.
  • To explore mechanisms of oncogene independence in T-ALL.

Main Methods:

  • Development of a tetracycline-regulated mouse model of T-ALL driven by the Lmo2 oncogenic transcription factor.
  • Analysis of leukemia relapse following Lmo2 withdrawal.
  • Investigation of tumor suppressor gene mutations, including Ikzf1 (Ikaros), in relapsed leukemias.
  • Assessment of TAL1's role in human T-ALL cell lines with SIL-TAL1 deletions.

Main Results:

  • Thymus-resident pre-Leukemic Stem Cells (pre-LSCs) require continuous Lmo2 expression for maintenance.
  • Most T-ALL leukemias relapsed despite Lmo2 withdrawal, often acquiring a mature phenotype.
  • Relapse was associated with mutations or loss of tumor suppressor genes, notably Ikzf1 (Ikaros).
  • Targeted deletion of Ikzf1 conferred Lmo2-independence.
  • The transcription factor TAL1 was dispensable in human T-ALL cell lines with SIL-TAL1 deletions.

Conclusions:

  • T-ALL exhibits an evolution of oncogene addiction in both murine and human contexts.
  • Loss of Ikaros is a key mechanism promoting T-ALL lymphoblast self-renewal independently of initiating oncogenic transcription factors.
  • These findings highlight potential therapeutic strategies targeting oncogene-independent mechanisms in T-ALL relapse.