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How TET2 gene deficiency fuels development of acute myeloid leukemia

Discovery could lead to targeted new treatments for aggressive cancer of the bone marrow

Date:
August 17, 2023
Source:
City of Hope
Summary:
Scientists have identified how low levels of the TET2 gene fuel the rapid growth of acute myeloid leukemia in animal models.
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Scientists at City of Hope, one of the largest cancer research and treatment organizations in the United States, have identified how low levels of the TET2 gene fuel the rapid growth of acute myeloid leukemia in animal models. Cell Stem Cell recently published the study.

A team led by Jianjun Chen, Ph.D., the Simms/Mann Family Foundation Chair in Systems Biology at Beckman Research Institute of City of Hope, found that TET2 deficiency sets off a cascade of biochemical changes that enhance the bone marrow cancer's ability to spread. These changes include:

  • Driving the movement of malignant stem cells from the bloodstream to the bone marrow region where they originated. This home microenvironment, called a niche, protects the cells' survival and ability to divide and self-replicate.
  • Increasing the expression of a protein called TSPAN13 that signals leukemia stem cells to travel back to the bone marrow niche
  • Leading to the buildup of a methylated form of the RNA base cytosine that enhances TSPAN13 messenger RNA's stability, resulting in the increased expression of TSPAN13 protein
  • Activating a signaling pathway called the TSPAN13/CXCR4 axis that increases malignant stem cells' return (i.e., homing) to the bone marrow niche and self-replication, thereby leading to the rapid development of leukemia.

By expanding understanding of the multiple ways that TET2 influences the development of acute myeloid leukemia, the discovery points to new potential therapeutic targets for treating the disease.

"This study provides novel insights into the cellular and molecular mechanisms underlying the development of acute myeloid leukemia," Chen said. "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 deficiency."

Acute myeloid leukemia is distinguished by the rapid division and spread of immature leukemia stem cells. More than half of patients relapse, and the five-year survival rate is only 30%. Figuring out how to destroy these cells is crucial to effectively treating the disease.

TET2 deficiency cooperates with leukemia-related oncoproteins resulting from chromosomal abnormalities or gene mutations to drive the development of leukemia and enhance malignant stem cells' ability to divide and spread. Until now, however, the cellular and molecular mechanisms underlying these processes have remained murky.

In analyzing data from the Cancer Genome Atlas, Chen and his colleagues found that lower expression or mutation of TET2 was associated with a poor prognosis and shorter overall survival rates for patients. Compared to healthy control subjects, TET2 expression was significantly suppressed in acute myeloid leukemia patients. This led the team to investigate the clinical relevance of TET2 in the development of the disease.

The research was partly supported by grants from the National Institutes of Health (R01 CA214965, R01 CA243386, R01 CA236399, R01 CA271497, R01 DK124116 and R01 CA280389), 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 (PNC22-261362 and T32 CA186895).


Story Source:

Materials provided by City of Hope. Original written by Zen Logsdon. Note: Content may be edited for style and length.


Journal Reference:

  1. Yangchan Li, Meilin Xue, Xiaolan Deng, Lei Dong, Le Xuan Truong Nguyen, Lili Ren, Li Han, Chenying Li, Jianhuang Xue, Zhicong Zhao, Wei Li, Ying Qing, Chao Shen, Brandon Tan, Zhenhua Chen, Keith Leung, Kitty Wang, Srividya Swaminathan, Ling Li, Mark Wunderlich, James C. Mulloy, Xiaobo Li, Hao Chen, Bin Zhang, David Horne, Steven T. Rosen, Guido Marcucci, Mingjiang Xu, Zejuan Li, Minjie Wei, Jingyan Tian, Baiyong Shen, Rui Su, Jianjun Chen. TET2-mediated mRNA demethylation regulates leukemia stem cell homing and self-renewal. Cell Stem Cell, 2023; 30 (8): 1072 DOI: 10.1016/j.stem.2023.07.001

Cite This Page:

City of Hope. "How TET2 gene deficiency fuels development of acute myeloid leukemia." ScienceDaily. ScienceDaily, 17 August 2023. <www.sciencedaily.com/releases/2023/08/230817164043.htm>.
City of Hope. (2023, August 17). How TET2 gene deficiency fuels development of acute myeloid leukemia. ScienceDaily. Retrieved June 19, 2024 from www.sciencedaily.com/releases/2023/08/230817164043.htm
City of Hope. "How TET2 gene deficiency fuels development of acute myeloid leukemia." ScienceDaily. www.sciencedaily.com/releases/2023/08/230817164043.htm (accessed June 19, 2024).

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