Mutations in the TET2 gene are among the most common signatures of certain blood cancers such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The TET proteins, TET1-3, function in the demethylation of cytosine, one of the four bases found in DNA. Cytosine methylation is an epigenetic modification, a heritable change in the base’s structure that does not change the DNA sequence, that shuts down gene expression. The TET proteins are involved in the removal of this epigenetic mark and the potential reactivation of genes. Prior work from the lab of Dr. Iannis Aifantis at NYU School of Medicine showed that inactivation of Tet2 leads to aberrant proliferation and self-renewal of the hematopoietic stem and progenitor cells (HSPCs) that produce red and white blood cells. Now in the journal Cell, Dr. Aifantis, in collaboration with Drs. Benjamin Neel and Luisa Cimmino, generated a mouse model in which they first inactivated Tet2, recapitulating the abnormal HSPC behavior, and then reactivated Tet2. Renewed Tet2 expression led to generalized demethylation across the genome, reversal of aberrant proliferation, increased cell death through apoptosis, and differentiation of some HSPCs into myeloid cells. Importantly for AML and MDS patients, the team went on to show that administering vitamin C intravenously into mouse models of these diseases as well as patient-derived xenograft models – mice that are transplanted with human AML cells – increased TET activity and reduced the spread of the cancer cells. Finally, the investigators used vitamin C in combination with a drug used to treat ovarian cancer and found even better results, higher cell death among multiple cancer cell lines. They think the vitamin C sensitizes the cancer cells to the drug, and oncologists at NYU are already preparing to test the combination in MDS patients in a clinical trial. This research was supported in part by NYSTEM research award C030132 to Dr. Aifantis.
Watch the investigators describe these findings in the video below.
Cimmino L, Dolgalev I, Wang Y, Yoshimi A, Martin GH, Wang J, Ng V, Xia B, Witkowski MT, Mitchell-Flack M, Grillo I, Bakogianni S, Ndiaye-Lobry D, Martín MT, Guillamot M, Banh RS, Xu M, Figueroa ME, Dickins RA, Abdel-Wahab O, Park CY, Tsirigos A, Neel BG, Aifantis I. Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. Cell. 2017, Sep 7; 170(6): 1079-1095.