A new layer of gene control in blood development that is also modulated in cancer

May 16, 2022

By Christopher Vaughan

Every cell contains all the genes in the genome, but which genes are used to make a cell's functional proteins often comes down to the presence of chemical methylation “marks” at key spots in the genome. These methylation marks control the expression of genes, especially as cells develop from stem cells into progenitor cells and through many more steps to mature cells. 

These methylation marks particularly apear as 5mC, a master regulator of gene expression that can be removed by conversion into 5hmC. TET2 is one of a family of enzymes responsible for the conversion of 5mC into 5hmC, and it plays a key role in the normal formation of blood and immune cells. Importantly, mutations in TET2 are known to be an important initiating step in the development of multiple blood cancers.

Using several new technological approaches, Ravi Majeti, MD, PhD and his colleagues have investigated 5hmC in normal blood development and report on its modulation and association with gene expression across various types of cells, from blood stem and progenitor cells to mature blood cells. Further, this team, engineered TET2 mutations into human blood stem and progenitor cells to investigate the interplay between TET2 and 5hmC, and the effects of pharmacologic agents targeting this pathway. This work involved a collaboration between the Stanford team and Bluestar Genomics, who have pioneered assays of 5hmC across many tissues and diseases. The researchers reported their results in the journal Blood Cancer Discovery. The co-first authors were Yusuke Nakauchi, MD, PhD and Armon Azizi, BS. The senior author was RZ Cao Professor of Medicine Ravi Majeti, MD, PhD. Majeti is also assistant director of Ludwig Center for Cancer Stem Cell Research and Medicine, as well as a member of the Institute for Stem Cell Biology and Regenerative Medicine. 

They discovered that 5hmC is modulated during blood development and links with gene expression programs, suggesting it plays a direct role in gene regulation. Notably, 5hmC levels were decreased in TET2 mutant cells, particularly at regions involved in red blood cell development. This was striking as the TET2 mutant cells were poor at producing red blood cells. When transplanted into mice, these TET2 mutant human cells were found to expand in a way that was similar to what is observed in human individuals who acquire this mutation in their blood.

Lastly, vitamin C, or the approved therapeutic azacytidine, are known to have activity against mutant TET2 and TET2-mutant cells, and the Stanford team showed that these agents not only reversed the effects of mutant TET2 on red blood cell production and expansion in mice, but also increased the level of 5hmC at the same regions affected by mutation of TET2. These results support the model that 5hmC plays a vital role in normal blood cell activity and the development of cancer, particularly with mutations in TET2, and provide important insights for potential therapeutic interventions.