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Vitamin C a potential nontoxic therapy for TET-associated haematologic malignancies

Jairia Dela Cruz
11 Sep 2017

Vitamin C may halt the self-renewal of TET methylcytosine dioxygenase 2 (TET2)-deficient haematopoietic cells and suppress leukaemia progression, in addition to rendering the cells more susceptible to poly ADP ribose polymerase (PARP) inhibition, according to a study.

Vitamin C blocks leukaemia progression by acting as a pharmacological mimic to TET2 restoration, which particularly promotes DNA demethylation, differentiation and cell death in TET2-deficient cells, the investigators said. [Cell 2017;doi: 10.1016/j.cell.2017.07.032]

Demethylation involves the activation of genes that direct stem cells to mature or initiate a countdown toward self-destruction as part of normal turnover. Such process represents an anticancer safety mechanism, one that is disrupted in blood cancer patients with TET2 mutations, explained one of the corresponding investigators, Dr Benjamin Neel from the New York University School of Medicine.

TET2 mutations are common in haematologic malignancies, found in about 10 percent of patients with acute myeloid leukemia (AML), 30 percent of those with a form of preleukemia known as myelodysplastic syndrome (MDS), and nearly 50 percent of those with chronic myelomonocytic leukaemia (CMML). In these patients, signals that tell a blood stem cell to mature malfunction, leaving the cell to endlessly multiply and “self-renew.” [N Engl J Med 2009;360:2289–2301; Haematologica 2009;94:1676–1681]

“Conceivably, restoring TET2 function could provide therapeutic benefit to [the aforementioned] patients, but it remains unclear if TET2 deficiency is necessary for disease maintenance,” Neel and colleagues noted.

To address the issue, in vitro and in vivo experiments were performed using mice genetically engineered such that the TET2 gene in haematopoietic cells could be switched “on” and “off.” Results showed that sustained TET2 deficiency was indeed a requisite to aberrant self-renewal of the cells, and this abnormal cell behaviour was reversed upon TET2 restoration.

The loss of aberrant self-renewal capacity in TET2-restored mouse cells was associated with impaired proliferation, increased cell death and priming toward myeloid differentiation.

Furthermore, in cases where genetic TET2 restoration was not an option, treatment with vitamin C remarkably mimicked TET2 restoration by inducing DNA demethylation in TET2-deficient mouse cells and suppressed leukaemic colony formation and leukaemia progression of human patient-derived leukaemia cancer stem cells implanted in mice.

Vitamin C also drove DNA hypomethylation and expression of a TET2-dependent gene signature in human AML cell lines. In combination with olaparib, vitamin C interestingly conferred increased vulnerability to PARP inhibition on the cells, causing greater loss in their viability to repair DNA damage as compared with either agent alone.

“Hence, vitamin C treatment can enhance TET2 function in human leukaemia cells in a manner similar to the effects of TET2 restoration in mouse hematopoietic stem and progenitor cells,” the investigators said, adding that the increased vulnerability to PARP inhibitors puts forward a safe and effective combination strategy to selectively target TET deficiency in cancer.

“We're excited by the prospect that high-dose vitamin C might become a safe treatment for blood diseases caused by TET2-deficient leukaemia stem cells, most likely in combination with other targeted therapies,” said Neel in a news release.

Neel and colleagues recommended that in light of the present data, future clinical trials should incorporate high-dose vitamin C as an adjuvant to standard chemotherapy/demethylating therapy, especially for TET2-deficient neoplasms, and predict further improvement in efficacy with the addition of PARP inhibition.

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