Development of Leukemia and Lymphoma Traced to Loss of T-cell Differentiation Controls

Loss of TET protein tumor suppressor activity disrupts white blood cell development, which can lead to leukemia, lymphoma, and other cancers.

DNA methylation is an epigenetic mechanism that is important for controlling gene expression. TET proteins are among the factors taking part in this critical process. The proteins encoded by TET (ten-eleven translocation) family genes are demethylases that oxidize 5-methylcytosine in DNA to 5-hydroxymethylcytosine and other oxidation products.

To learn why TET proteins promote cancer development, investigators at the La Jolla Institute for Allergy and Immunology (CA, USA) genetically engineered a line of mice to lack the genes for both TET2 (TET methylcytosine dioxygenase 2) and TET3 (TET methylcytosine dioxygenase 3) in CD4+CD8+ double-positive T-cells. These mice developed a lethal disease resembling lymphoma within weeks of birth, their spleens and livers overwhelmed with invariant natural killer T-cells (iNKT cells), a normally rare kind of T-cell.

The investigators reported in the November 21, 2016, online edition of the journal Nature Immunology that TET2-TET3 double-knockout (DKO) iNKT cells displayed pronounced skewing toward the NKT17 lineage, with increased DNA methylation and impaired expression of genes encoding key lineage-specifying factors.

Transfer of purified TET2-TET3 DKO iNKT cells into immunocompetent recipient mice resulted in an uncontrolled expansion that developed into a lymphoproliferative disease as lethal as that seen in TET2/3 mutant mice.

"We knew that TET proteins were involved in human cancer but we did not know how they regulated T-cell development," said first author Dr. Angeliki Tsagaratou, a researcher at the La Jolla Institute for Allergy and Immunology. "In the new study we saw huge increases in the proliferation of the special iNKT cells in TET2/3 mutant mice. Once growth control was lost, those cells underwent the kind of malignant transformation that gives rise to T-cell lymphoma in humans. When TET proteins are lost, iNKT cells that lack them apparently become trapped in an immature, highly proliferative state. Unlike normal cells, they cannot switch off growth-promoting genes: they just keep dividing."

"Right now we do not know how TET mutations specifically contribute to either T-cell lymphomas or leukemias. But we think these mutations are early events in both," said Dr. Tsagaratou. "The search is on is to discover additional cancer-causing genes downstream of TET mutations that drive uncontrolled cell division in either context. Identification of additional factors would give us a broad idea of all steps in pathway and provide multiple targets to hit."

Related Links:
La Jolla Institute for Allergy and Immunology