Abstract
Simple SummaryThe inhibitors of BET proteins represent a promising class of therapeutic agents that target the oncogenic activity of MYC and repress DLBCL cell migration, but the mechanism of such repression remains elusive. Herein, we found that BET inhibitor JQ1 abrogated the amoeboid movement of DLBCL cells through a small GTPase-driven mechanism, including both restrained RAS signaling and MYC-mediated suppression of GTP-RhoA activity. BET inhibition drastically increased the expression of a GTPase regulatory protein, the IQ motif containing GTPase activating protein 3 (IQGAP3), in DLBCL. Proteomics-based re-stratification identified a specific subgroup of DLBCL patients whose tumors harbored an enhanced PI3K activity and had an inferior survival, whereas a lower IQGAP3 expression level further portended a very dismal outcome for those patients. The inhibitors of both BET and RAS (through attenuated PI3K signaling) activities effectively ameliorated the outspread of in vivo DLBCL tumors, indicating the potential of their synergism in the treatment of specific DLBCL subtypes.Phenotypic heterogeneity and molecular diversity make diffuse large B-cell lymphoma (DLBCL) a challenging disease. We recently illustrated that amoeboid movement plays an indispensable role in DLBCL dissemination and inadvertently identified that the inhibitor of bromodomain and extra-terminal (BET) proteins JQ1 could repress DLBCL migration. To explore further, we dissected the impacts of BET inhibition in DLBCL. We found that JQ1 abrogated amoeboid movement of DLBCL cells through both restraining RAS signaling and suppressing MYC-mediated RhoA activity. We also demonstrated that BET inhibition resulted in the upregulation of a GTPase regulatory protein, the IQ motif containing GTPase activating protein 3 (IQGAP3). IQGAP3 similarly exhibited an inhibitory effect on RAS activity in DLBCL cells. Through barcoded mRNA/protein profiling in clinical samples, we identified a specific subgroup of DLBCL tumors with enhanced phosphatidylinositol-3-kinase (PI3K) activity, which led to an inferior survival in these patients. Strikingly, a lower IQGAP3 expression level further portended those with PI3K-activated DLBCL a very dismal outcome. The inhibition of BET and PI3K signaling activity led to effective suppression of DLBCL dissemination in vivo. Our study provides an important insight into the ongoing efforts of targeting BET proteins as a therapeutic approach for DLBCL.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adulthood worldwide
We demonstrated that signal transducer and activator of transcription 3 (STAT3)-coordinated amoeboid movement led to the dissemination of diffuse large B-cell lymphoma (DLBCL) cells, and strategies aiming at suppressing DLBCL cell migration significantly reduced the tumor burden in an in vivo xenograft model [16]
When added to cells deployed in the collagen solution (Figure 1a), both JQ1 and AZD5153 significantly reduced the migration of DLBCL cells (Figure 1b,c)
Summary
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adulthood worldwide. BET proteins play a crucial role as epigenetic readers [4] through binding to acetylated lysine residues on histone tails to modulate the expression of key genes defining the biology of normal cells and of oncogenes engaging in tumorigenesis [4,5,6]. Several small-molecule inhibitors have been developed to competitively interfere with the histone-binding capacity and epigenetic activity of BET proteins [7,8]. Through targeting of MYC dependence in cancer cells [7,9], they have shown promising efficacy in a variety of solid tumors and hematological malignancies [5], including DLBCL [8,10]
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