Abstract
Loss-of-function TET2 mutations (
TET2
MT
) are common in myeloid neoplasia. TET2, a DNA dioxygenase, requires 2-oxoglutarate and Fe(II) to oxidize 5-methylcytosine.
TET2
MT
thus result in hypermethylation and transcriptional repression. Ascorbic acid (AA) increases dioxygenase activity by facilitating Fe(III)/Fe(II) redox reaction and may alleviate some biological consequences of
TET2
MT
by restoring dioxygenase activity. Here, we report the utility of AA in the prevention of
TET2
MT
myeloid neoplasia (MN), clarify the mechanistic underpinning of the TET2-AA interactions, and demonstrate that the ability of AA to restore TET2 activity in cells depends on N- and C-terminal lysine acetylation and nature of
TET2
MT
. Consequently, pharmacologic modulation of acetyltransferases and histone deacetylases may regulate TET dioxygenase-dependent AA effects. Thus, our study highlights the contribution of factors that may enhance or attenuate AA effects on TET2 and provides a rationale for novel therapeutic approaches including combinations of AA with class I/II HDAC inhibitor or sirtuin activators in
TET2
MT
leukemia.
Using TET2- and ascorbic acid deficient model systems Guan et al show that long term treatment with ascorbic acid delays myeloid neoplasia in mice and reveal a complex interplay of post-translational modification of lysine residues that modulate TET2 activity in neoplastic evolution.
