1. Introduction
Glucocorticoid
is widely used due to its effective anti-inflammatory and
immunosuppressing effect [1] . Dexamethasone (Dex), a classical
glucocorticoid, is recognized as one of the standard
therapeutics
in hematological malignancies including leukemia and lymphoma, and the
clinical effect is much better than other Glucocorticoids [2-4]. Dex
exerts its anti-tumor effects primarily by binding to and subsequently
activating glucocorticoid receptor (GR) [5, 6]. After translocating
into the nuclear region, activated GR commonly regulates the expression
of its target genes via binding to the glucocorticoid response element
(GRE) [7, 8]. Although the function of GR has been studied for
decades, its precise antitumor mechanism has not been clearly clarified
yet.
DOT1L
(disruptor of telomere silencing 1 like) is the sole methytransferase
which carries out the methylation of histone H3 at lysine 79 [9].
Previous research have reported that DOT1L is linked to multiple
biological processes, such as telomere silencing, gene expression
regulation, cell aging, and DNA damage response [10-12]. Recently,
it has been proved that DOT1L has a crucial role in the initiation and
progression of various tumour types, such as lung cancer, breast cancer,
ovarian cancer, renal clear cell carcinoma, and neuroblastoma
[13-16]. Notably, DOT1L is strongly correlated with MLL-rearranged
leukemia [17]. DOT1L leads to aberrant H3K79 methylation that
contributes to the overexpression of
MLL target oncogenes such asMEIS1 and HOXA9 . Therefore, DOT1L is considered as a newly
therapeutic target against MLL-rearranged leukemia and the corresponding
inhibitors are investigating in clinical trials [18-20]. However, it
remains elusive whether DOT1L is linked to B cell lymphoma and whether
DOT1L
can be regulated by Dex.
Our work shows that DOT1L plays an oncogenic role in B lymphoma cells
and Dex downregulates DOT1L via GR activation. Besides, Dex decreases
DOT1L expression in Dex-sensitive B lymphoma cells and MLL-rearranged
leukemia cells, but not in Dex-insensitive acute monocytic leukemia
cells, suggesting that DOT1L may be a underlying novel indicator of Dex
sensitivity against hematological malignancies.