Understanding How TET2 Gene Deficiency May Fuel Development of AML

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Researchers may have identified how the TET2 gene may fuel rapid cancer growth in patients with acute myeloid leukemia (AML), according to a recent study published by Li et al in Cell Stem Cell.


AML is distinguished by the rapid division and metastasis of immature leukemia stem cells. More than 50% of patients who are treated for leukemia relapse, and the 5-year survival rate is 30%. Figuring out how to destroy these cells may be crucial to effectively treating the disease.

TET2 deficiencies cooperate with leukemia-related oncoproteins resulting from chromosomal abnormalities or gene mutations to drive the development of leukemia and enhance the malignant stem cells’ ability to divide and metastasize. Prior to the new study, the cellular and molecular mechanisms underlying these processes were uncertain.

Study Methods and Results

In this study, the researchers analyzed data from The Cancer Genome Atlas and discovered that the expression or mutation of TET2 was associated with poorer prognoses and shorter overall survival rates for patients with AML. Compared with healthy controls, TET2 expression was significantly suppressed in patients with AML.

The researchers also determined that TET2 deficiencies were capable of setting off a cascade of biochemical changes that enhanced AML’s ability to metastasize. Among the changes were:

  • Driving the movement of malignant stem cells from the bloodstream to the bone marrow niche where they originated—a microenvironment that may allow for the cells’ survival and ability to divide and self-replicate
  • Increasing the expression of the TSPAN13 protein that signals for leukemia stem cells to travel back to the bone marrow niche
  • Causing the buildup of a methylated form of the RNA base cytosine that enhances TSPAN13 messenger RNA’s stability, resulting in the increased expression of the TSPAN13 protein
  • Activating a signaling pathway called the TSPAN13/CXCR4 axis that increases malignant stem cells’ return to the bone marrow niche and self-replication, leading to the rapid development of leukemia.


By expanding the understanding of the multiple ways in which TET2 may influence the development of AML, the recent findings suggest new potential therapeutic targets for treating patients with the disease.

“This study provides novel insights into the cellular and molecular mechanisms underlying the development of [AML],” emphasized senior study author Jianjun Chen, PhD, the Simms/Mann Family Foundation Chair in Systems Biology at the Beckman Research Institute at the City of Hope. “Our findings highlight the therapeutic potential of reactivating TET2 signaling in patients with TET2 mutations or transcriptional suppression. Equally exciting, this strategy could be applied to other types of cancer that feature TET2 deficiencies,” he concluded.

Disclosure: The research in this study was partly supported by grants from the National Institutes of Health, the Simms/Mann Family Foundation, Leukemia Research Foundation New Investigator Research Grant, The Margaret E. Early Medical Research Trust, and the American Association for the Study of Liver Diseases Foundation. For full disclosures of the study authors, visit

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