Increased Expression of SETDB1 Predicts Poor Prognosis in Multiple Myeloma

Abstract

Several genes on chromosome 1q21 region predict a high risk of multiple myeloma (MM); however, the underlying molecular pathology remains elusive. Overexpression, amplification, or activation of SET Domain Bifurcated 1 (SETDB1), which is located on 1q21, is closely associated with poor prognosis of many human solid malignancies. In our study, upregulation of SETDB1 might indicate an unfavorable prognosis of MM using bioinformatics analysis from GEO databases and MMRF-CoMMpass. Here, increased SETDB1 expression was observed in the plasma cells from newly diagnosed multiple myeloma patients compared to those from the normal controls. Meanwhile, SETDB1 overexpression was the result of increased copy numbers of SETDB1 gene. In MM patients, the Kaplan-Meier analysis was employed to demonstrate that increased SETDB1 expression was associated with shorter overall survival (OS) and event-free survival (EFS). Besides, we conducted multifactorial cox regression analysis to state that SETDB1 expression was an independent biomarker for OS and EFS. MM patients with higher SETDB1 expression showed higher levels of beta-2 microglobulin (β2M), lactate dehydrogenase (LDH), and bone marrow biopsy plasma cells (BMPC) and lower levels of haemoglobin (HGB). Functional enrichment analysis suggested that SETDB1 could promote cell cycle progression in myeloma. Finally, we observed that SETDB1 was distinctly correlated with tumor immunity in MM. SETDB1 expression in myeloma cells was positively correlated with CD56dim natural killer cells but negatively correlated with infiltrating levels of type17 T helper cells, effector memory CD8 T cells, activated dendritic cells, and natural killer T cells from whole bone marrow (WBM) biopsies. Taken together, these results indicated that SETDB1 could be used as a novel biomarker for predicting the prognosis of MM patients.

Mosaic chromosomal alterations detected in men living with HIV and the relationship to non-Hodgkin lymphoma

“…In addition, the highest mCA cell fraction was observed in a man who was diagnosed with BL within days of baseline. His mCAs encompassed SETDB1 and SRSF2, both of which are mutated in other hematologic malignancies [28][29][30].…”

SETDB1 as a cancer target: challenges and perspectives in drug design

“…This KMT is a potential target in multiple signaling pathways of carcinogenesis. 31,32,34,78,79 Several studies have reported that the overexpression of SETDB1 and its activity are related to aggressive tumor phenotypes, 80 such as in breast, 35,81,82 colon, 83,84 liver 32,33,85 and lung cancers, 78,[86][87][88][89] as well as in myeloid leukemia. 90,91 Furthermore, lung cancer studies have shown that the upregulation of the protein was vital for its rapid growth and proliferation.…”

“…[128][129][130][131] Given the intricacy and significance of the immune response in cancer survival, some research has looked at the influence and function of SETDB1 in this scenario. 80,95,[132][133][134] For example, Griffin et al demonstrates SETDB1 as an immune escaping mediator and immune sensitivity modulator of cancer cells. More notably, the study demonstrated that, in patients with advanced renal cell carcinoma, SETDB1 amplification or overexpression also predicted poor prognosis in response to programmed death 1 (PD1) blockage but not mTOR inhibition.…”

SETDB1: A perspective into immune cell function and cancer immunotherapy

“…1. SETDB1 suppresses Th17 transcription and upregulates production of CD56dim natural killer cells [23]. SETDB1 suppresses IL‐6 production [13].…”

“…As we previously mentioned, Hachiya and colleagues suggested that IL-6 expression in macrophages is mediated by TLR4 and induced by SETDB1 depletion [13]; confirmation of direct SETDB1-mediated expression still needs to be confirmed in future studies. Xiang and colleagues characterized the mechanism associating SETDB1 overexpression with poor prognosis of multiple myeloma [23]. Higher levels of SETDB1 correlates with higher levels of beta-2 microglobulin, lactate dehydrogenase (LDH), bone marrow biopsy plasma cells, and lower haemoglobin levels.…”