Regulatory network of BLIMP1, IRF4, and XBP1 triad in plasmacytic differentiation and multiple myeloma pathogenesis

Tang, Ting; Chan, Yee Teng; Cheong, Heng Choon; Cheok, Yi Ying; Anuar, Nur Adila; Looi, Chung Yeng; Gan, Gin Gin; Wong, Won Fen

doi:10.1016/j.cellimm.2022.104594

Cited by 7 publications

(5 citation statements)

References 119 publications

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“…For comparison, we used cells expressing non-targeting control shRNA. As expected, IRF4 silencing depleted mRNAs encoding IRF4 itself and other previously characterized IRF4 targets such as MYC 14,44 , PRDM1 13,14,17,19 and XBP1 17,19 (Fig. S4A).…”

Section: Ire1 and Irf4 Regulate A Highly Overlapping Set Of Cell Cycl...supporting

confidence: 82%

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IRF4 mediates non-enzymatic dependency on IRE1 in Multiple Myeloma cells

Oikonomidi,

Kameswaran,

Pham

et al. 2024

Preprint

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Multiple Myeloma (MM) arises through oncogenic transformation of immunoglobulin-secreting plasma cells. MM often co-opts the endoplasmic-reticulum (ER) stress mitigator, inositol-requiring enzyme 1 (IRE1) to sustain malignant growth. While certain MMs require enzymatic IRE1-dependent activation of the ER-homeostatic transcription factor XBP1s, others display a non-enzymatic dependency on IRE1 that is not yet mechanistically understood. Interferon regulatory factor 4 (IRF4) stimulates gene programs that promote immune-cell proliferation and plays an essential role in MM. Here we show that the non-enzymatic reliance on IRE1 in MM entails IRF4. IRE1 silencing increased inhibitory phosphorylation of IRF4, disrupting its chromatin-binding activity and mRNA transcription. IRF4 knockdown recapitulated, whereas IRF4 re-expression reversed the anti-proliferative phenotype of IRE1 silencing. Mechanistic studies revealed that IRF4 engages the E2F1 and CDC25A genes and promotes CDK2 activation to drive cell cycle progression. Our results uncover an unexpected functional link between IRE1 and IRF4 in MM.

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Section: Ire1 and Irf4 Regulate A Highly Overlapping Set Of Cell Cycl...supporting

confidence: 82%

“…The transcriptional regulator Interferon response factor 4 (IRF4) orchestrates B-cell activation as well as plasma-cell differentiation and survival [13][14][15][16][17] . During plasma-cell differentiation, IRF4 cooperates nonredundantly with the IRE1-XBP1s pathway, most prominently by inducing transcription of PRDM1/BLIMP1 18,19 .…”

Section: Introductionmentioning

confidence: 99%

IRF4 mediates non-enzymatic dependency on IRE1 in Multiple Myeloma cells

Oikonomidi,

Kameswaran,

Pham

et al. 2024

Preprint

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“…S10A). 40 MYD88 , a gene associated with lymphoplasmacytic lymphomas, was also detected in VAR08 tumor cells. 41 The major determinants of plasma cell differentiation harbored within VAR08 were thus identified (Fig.…”

Section: Resultsmentioning

confidence: 98%

Histologic variants in bladder cancer harbor aggressive molecular features including TM4SF1 expression and a CA125+ cell state

Yang,

Song,

Yip

et al. 2024

Preprint

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Histologic variant (HV) subtypes of bladder cancer are clinically aggressive tumors that are more resistant to standard therapy compared to conventional urothelial carcinoma (UC). Little is known about the transcriptional programs that account for the morphological and biological differences in HV tumors. To investigate the tumor biology of HV bladder cancers, we generated a single cell RNA sequencing (scRNA-seq) atlas of nine HV tumors and three UC tumors. Our analyses revealed a tumor cell state specific to HVs that is characterized by expression of MUC16 (CA125), KRT24, and WISP2. This CA125+ cell state bears transcriptional hallmarks of epithelial-mesenchymal transition, is enriched in metastases, is predicted to be highly chemotherapy resistant, and is linked with poor survival, suggesting that this cell state plays an important role in the aggressive biology of HV tumors. Our analyses also provide novel evidence of transcriptional "mimicry" between HVs and histologically similar non-urothelial cell types. Lastly, we identified higher expression of TM4SF1, a cell surface protein associated with cancer metastasis, in HV tumor cells compared to UC tumor cells. Finally, CAR T cells engineered against TM4SF1 protein demonstrated in vitro and in vivo activity against bladder cancer cell lines in a TM4SF1 expression-dependent manner, highlighting its potential as a therapeutic target in bladder cancer.

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“…Two key transcription factors for plasma cell differentiation are IRF4 and Blimp1/PRDM1. Whilst IRF4 induces plasma cell differentiation by directing immunoglobulin class switching, proliferation, and survival, BLIMP1 acts as a transcriptional repressor that represses B-cell features ( 102 ). For the rat anti-human-IRF4, clone 3E4 cross-reaction with porcine cells has been demonstrated ( 103 ) and preliminary data suggest cross-reaction with chicken cells (personal communication, Dr. W. Gerner).…”

Section: B Cellsmentioning

confidence: 99%

Delineation of chicken immune markers in the era of omics and multicolor flow cytometry

Härtle,

Sutton,

Vervelde

et al. 2024

Front. Vet. Sci.

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Multiparameter flow cytometry is a routine method in immunological studies incorporated in biomedical, veterinary, agricultural, and wildlife research and routinely used in veterinary clinical laboratories. Its use in the diagnostics of poultry diseases is still limited, but due to the continuous expansion of reagents and cost reductions, this may change in the near future. Although the structure and function of the avian immune system show commonalities with mammals, at the molecular level, there is often low homology across species. The cross-reactivity of mammalian immunological reagents is therefore low, but nevertheless, the list of reagents to study chicken immune cells is increasing. Recent improvement in multicolor antibody panels for chicken cells has resulted in more detailed analysis by flow cytometry and has allowed the discovery of novel leukocyte cell subpopulations. In this article, we present an overview of the reagents and guidance needed to perform multicolor flow cytometry using chicken samples and common pitfalls to avoid.

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Regulatory network of BLIMP1, IRF4, and XBP1 triad in plasmacytic differentiation and multiple myeloma pathogenesis

Cited by 7 publications

References 119 publications

IRF4 mediates non-enzymatic dependency on IRE1 in Multiple Myeloma cells

IRF4 mediates non-enzymatic dependency on IRE1 in Multiple Myeloma cells

Histologic variants in bladder cancer harbor aggressive molecular features including TM4SF1 expression and a CA125+ cell state

Delineation of chicken immune markers in the era of omics and multicolor flow cytometry

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