Decreased SATB1 expression promotes AML cell proliferation through NF-κB activation

Luo, Xiaodan; Xu, Lihua; Wu, Xiaohong; H, Tan; Liu, Lian

doi:10.1186/s12935-019-0850-x

Cited by 6 publications

(7 citation statements)

References 43 publications

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“… 38 CCNA1 has previously been identified as a PRC2 target in AML, and decreased expression of SATB1 resulted in increased cell proliferation in AML. 39 , 40 Importantly, we also show that these genes are downregulated in more advanced stages of MM, highlighting the potential relevance of their silencing as the disease progresses. Loss of the EZH2- PVT1 axis was also associated with the upregulation of 21 tumor suppressor genes.…”

Section: Discussionsupporting

confidence: 54%

<i>PVT1</i> interacts with polycomb repressive complex 2 to suppress genomic regions with pro-apoptotic and tumour suppressor functions in multiple myeloma

Nylund¹,

Garrido-Zabala²,

Párraga³

et al. 2023

haematol

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Multiple myeloma is a heterogeneous haematological disease that originates from the bone marrow and is characterized by the monoclonal expansion of malignant plasma cells. Despite novel therapies, multiple myeloma remains clinically challenging. A common feature among patients with poor prognosis is the increased activity of the epigenetic silencer EZH2, which is the catalytic subunit of the PRC2. Interestingly, the recruitment of PRC2 lacks sequence specificity and, to date, the molecular mechanisms that define which genomic locations are destined to PRC2-mediated silencing remain unknown. The presence of a lncRNA-binding pocket on EZH2 suggests that lncRNAs could potentially mediate PRC2 recruitment to specific genomic regions. Here, we coupled RIP-seq, RNA-Seq and ChIP-seq analysis of human multiple myeloma primary cells and cell lines to identify potential lncRNA partners to EZH2. We found that the lncRNA plasmacytoma variant translocation 1 (PVT1) directly interacts with EZH2 and is overexpressed in patients with a poor prognosis. Moreover, genes predicted to be targets of PVT1 exhibited H3K27me3 enrichment and were associated with pro-apoptotic and tumour suppressor functions. In fact, PVT1 inhibition independently promotes the expression of the PRC2 target genes ZBTB7C, RNF144A and CCDC136. Altogether, our work suggests that PVT1 is an interacting partner in PRC2-mediated silencing of tumour suppressor and pro-apoptotic genes in multiple myeloma, making it a highly interesting potential therapeutic target.

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Section: Discussionsupporting

confidence: 54%

<i>PVT1</i> interacts with polycomb repressive complex 2 to suppress genomic regions with pro-apoptotic and tumour suppressor functions in multiple myeloma

Nylund¹,

Garrido-Zabala²,

Párraga³

et al. 2023

haematol

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“…Here, we demonstrate that both p65 and p50 are present in the nuclei of A. phagocytophilum-infected cells for at least 7 days of infection, although p65 is constitutively expressed in uninfected HL-60 cells (62). The presence of NF-κB p105 in nuclear lysates was not anticipated, but is well-documented with stimulation (63)(64)(65); whether it would provide IκB-like inhibitory function in this circumstance is not known, but likely.…”

Section: Discussionmentioning

confidence: 78%

Anaplasma phagocytophilum Activates NF-κB Signaling via Redundant Pathways

Dumler

Lichay

Chen

et al. 2020

Front. Public Health

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Anaplasma phagocytophilum subverts neutrophil function permitting intracellular survival, propagation and transmission. Sustained pro-inflammatory response, recruitment of new host cells for population expansion, and delayed apoptosis are associated with prolonged nuclear presence of NF-κB. We investigated NF-κB signaling and transcriptional activity with A. phagocytophilum infection using inhibitors of NF-κB signaling pathways, and through silencing of signaling pathway genes. How inhibitors or silencing affected A. phagocytophilum growth, inflammatory response (transcription of the κB-enhanced genes CXCL8 and MMP9), and NF-κB signaling pathway gene expression were tested. Among A. phagocytophilum-infected HL-60 cells, nuclear NF-κB p50, p65, and p52 were detected by immunoblots or iTRAQ proteomics. A. phagocytophilum growth was affected most by the IKKαβ inhibitor wedelolactone (reductions of 96 to 99%) as compared with SC-514 that selectively inhibits IKKβ, illustrating a role for the non-canonical pathway. Wedelolactone inhibited transcription of both CXCL8 (p = 0.001) and MMP9 (p = 0.002) in infected cells. Compared to uninfected THP-1 cells, A. phagocytophilum infection led to >2-fold down regulation of 64 of 92 NF-κB signaling pathway genes, and >2-fold increased expression in only 4. Wedelolactone and SC-514 reversed downregulation in all 64 and 45, respectively, of the genes downregulated by infection, but decreased expression in 1 gene with SC-514 only. Silencing of 20 NF-κB signal pathway genes increased bacterial growth in 12 (IRAK1, MAP3K1, NFKB1B, MAP3K7, TICAM2, TLR3, TRADD, TRAF3, CHUK, IRAK2, LTBR, and MALT1). Most findings support canonical pathway activation; however, the presence of NFKB2 in infected cell nuclei, selective non-canonical pathway inhibitors that dampen CXCL8 and MMP9 transcription with infection, upregulation of non-canonical pathway target genes CCL13 and CCL19, enhanced bacterial growth with TRAF3 and LTBR silencing provide evidence for non-canonical pathway signaling. Whether this impacts distinct inflammatory processes that underlie disease, and whether and how A. phagocytophilum subverts NF-κB signaling via these pathways, need to be investigated.

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“…5F , which show that G2/M checkpoint-associated gene sets were downregulated in cells harboring Y149F/Y334F double and Y149 single mutations, while anti-apoptosis-associated gene sets were downregulated in Y149F/Y334F double mutation cells. Among the genes associated with G2/M cell cycle progression and anti-apoptosis that were differentially expressed (adjusted p value < 0.05 and FC > 1.5) and relevant in myeloid malignancies 54 – 59 , we found SMAD3 , CCND2 , KIF5B , BCL2 , BCL2A1 , and SATB1 (Fig. 5G ).…”

Section: Resultsmentioning

confidence: 92%

Tyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity

Itonaga,

Mookhtiar,

Greenblatt

et al. 2024

Nat Commun

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An important epigenetic component of tyrosine kinase signaling is the phosphorylation of histones, and epigenetic readers, writers, and erasers. Phosphorylation of protein arginine methyltransferases (PRMTs), have been shown to enhance and impair their enzymatic activity. In this study, we show that the hyperactivation of Janus kinase 2 (JAK2) by the V617F mutation phosphorylates tyrosine residues (Y149 and Y334) in coactivator-associated arginine methyltransferase 1 (CARM1), an important target in hematologic malignancies, increasing its methyltransferase activity and altering its target specificity. While non-phosphorylatable CARM1 methylates some established substrates (e.g. BAF155 and PABP1), only phospho-CARM1 methylates the RUNX1 transcription factor, on R223 and R319. Furthermore, cells expressing non-phosphorylatable CARM1 have impaired cell-cycle progression and increased apoptosis, compared to cells expressing phosphorylatable, wild-type CARM1, with reduced expression of genes associated with G2/M cell cycle progression and anti-apoptosis. The presence of the JAK2-V617F mutant kinase renders acute myeloid leukemia (AML) cells less sensitive to CARM1 inhibition, and we show that the dual targeting of JAK2 and CARM1 is more effective than monotherapy in AML cells expressing phospho-CARM1. Thus, the phosphorylation of CARM1 by hyperactivated JAK2 regulates its methyltransferase activity, helps select its substrates, and is required for the maximal proliferation of malignant myeloid cells.

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Decreased SATB1 expression promotes AML cell proliferation through NF-κB activation

Cited by 6 publications

References 43 publications

<i>PVT1</i> interacts with polycomb repressive complex 2 to suppress genomic regions with pro-apoptotic and tumour suppressor functions in multiple myeloma

<i>PVT1</i> interacts with polycomb repressive complex 2 to suppress genomic regions with pro-apoptotic and tumour suppressor functions in multiple myeloma

Anaplasma phagocytophilum Activates NF-κB Signaling via Redundant Pathways

Tyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity

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