In multiple myeloma, normal plasma cells transform into
malignant myeloma cells and produce large quantities of toxic abnormal immunoglobulin called monoclonal protein that can damage multiple organs.
Our group has 3 major goals: Develop novel therapeutic approaches based on centrosomal clustering To further develop our first prototype inhibitors of centrosomal clustering preclinically and to establish a robust and specific high throughput small molecule screen Discover key events in
myeloma pathogenesis To investigate the pivotal transition from the pre-
malignant, asymptomatic to
malignant, symptomatic stages of plasma
cell dyscrasias in order to understand the pathophysiology and thereby identify novel targets Translate small molecule therapeutics from bench to clinical trials To evaluate novel agents in the preclinical setting and to initiate early phase clinical trials in hematologic malignancies with focus on multiple
myeloma
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.