In addition to p53, there are other transcriptional activatory mechanisms that are not well understood for the most part and which operate in response to mitogenic stimulation (11, 12), transforming
growth factor - β (13, 14, 15), and
aberrant oncogenic signals (16, 17) or during a number
of cell differentiation processes (18, 19).
In addition to being integral to
cell biology, tyrosine kinases also present targets for new anticancer therapies: One
of the most highly touted, rationally designed anticancer compounds, Gleevec, inhibits an oncogenic tyrosine kinase whose
aberrant activity fuels the rampant
growth of cells in patients with chronic myeloid leukemia.
This is in accordance with previous reports that decitabine and 5 - azacytidine produce a marked synergistic effect in combination with suberoylanilide hydroxamic acid and romidepsin in T - lymphoma
cell lines by modulating
cell cycle arrest and apoptosis.26, 27 As a mechanism
of action, KMT2D mutations
of B - lymphoma
cells promote malignant outgrowth by perturbing methylation
of H3K4 that affect the JAK - STAT, Toll - like receptor, or B -
cell receptor pathway.28, 29 Here our study indicated that dual treatment with chidamide and decitabine enhanced the interaction
of KMT2D with the transcription factor PU.1, thereby inactivating the H3K4me - associated signaling pathway MAPK, which is constitutively activated in T -
cell lymphoma.13, 30,31 The transcription factor PU.1 is involved in the development
of all hematopoietic lineages32 and regulates lymphoid
cell growth and transformation.33
Aberrant PU.1 expression promotes acute myeloid leukemia and is related to the pathogenesis
of multiple myeloma via the MAPK pathway.34, 35 On the other hand, PU.1 is also shown to interact with chromatin remodeler and DNA methyltransferease to control hematopoiesis and suppress leukemia.36 Our data thus suggested that the combined action
of chidamide and decitabine may interfere with the differentiation and / or viability
of PTCL - NOS through a PU.1 - dependent gene expression program.