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Efficient Purification and LC-MS/MS-based Assay Development for Ten-Eleven Translocation-2 5-Methylcytosine Dioxygenase
Published on: October 15, 2018
Acute loss of TET function results in aggressive myeloid cancer in mice
Jungeun An1, Edahí González-Avalos1, Ashu Chawla1
1Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
Abstract:
TET-family dioxygenases oxidize 5-methylcytosine (5mC) in DNA, and exert tumour suppressor activity in many types of cancers. Even in the absence of TET coding region mutations, TET loss-of-function is strongly associated with cancer. Here we show that acute elimination of TET function induces the rapid development of an aggressive, fully-penetrant and cell-autonomous myeloid leukaemia in mice, pointing to a causative role for TET loss-of-function in this myeloid malignancy. Phenotypic and transcriptional profiling shows aberrant differentiation of haematopoietic stem/progenitor cells, impaired erythroid and lymphoid differentiation and strong skewing to the myeloid lineage, with only a mild relation to changes in DNA modification. We also observe progressive accumulation of phospho-H2AX and strong impairment of DNA damage repair pathways, suggesting a key role for TET proteins in maintaining genome integrity.
Insights
Loss of TET dioxygenase function rapidly causes aggressive myeloid leukemia in mice, highlighting their crucial role in preventing this cancer by maintaining genome integrity.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- TET-family dioxygenases are known tumor suppressors involved in DNA demethylation.
- Loss-of-function of TET proteins is linked to various cancers, even without direct mutations.
- The precise role of TET function loss in myeloid malignancies requires further elucidation.
Purpose of the Study:
- To investigate the direct causative role of TET loss-of-function in myeloid leukemia development.
- To characterize the phenotypic and transcriptional consequences of acute TET function elimination.
- To explore the impact of TET loss on DNA damage repair pathways.
Main Methods:
- Acute elimination of TET function in a mouse model.
- Phenotypic and transcriptional profiling of hematopoietic stem and progenitor cells.
- Analysis of DNA damage markers (phospho-H2AX) and repair pathway function.
Main Results:
- Acute TET loss rapidly induced aggressive, cell-autonomous myeloid leukemia in mice.
- Observed aberrant hematopoietic stem/progenitor cell differentiation, impairing erythroid/lymphoid lineages.
- Identified impaired DNA damage repair pathways and accumulation of DNA damage markers.
Conclusions:
- TET loss-of-function plays a causative role in myeloid leukemia.
- TET proteins are critical for maintaining genome integrity and preventing myeloid malignancies.
- Further research into TET-mediated DNA repair mechanisms in cancer is warranted.
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