The druggable transcription factor Fli-1 regulates T cell immunity and tolerance in graft-versus-host disease

Schutt, Steven; Wu, Yongxia; Kharel, Arjun; Bastian, David; Choi, Hee-Jin; Sofi, M. Hanief; Mealer, Corey; Mims, Brianyell McDaniel; Nguyen, Hung; Liu, Chen; Helke, Kris; Cui, Weiguo; Zhang, Xian; Ben‐David, Yaacov; Yu, Xue-Zhong

doi:10.1172/jci143950

Cited by 8 publications

(7 citation statements)

References 71 publications

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“…Fli1 −/− studies demonstrated a down-regulation of genes associated with pro-inflammatory states, while genes with anti-inflammatory properties were up-regulated 79,80,82 . Additionally, metabolic pathways were also affected by FLI1 knockout in T cells, which displayed decreased glycolytic but increased oxidative phosphorylation activity 78 in line with our data. TCF7 is essential for a normal chromatin landscape in T cells 83 , acting mainly as a positive regulator on chromatin accessibility 39 and is critical for formation of long-term memory T cells 84 and Th17 longevity 38 .…”

Section: Discussionsupporting

confidence: 91%

Unveiling IRF4-steered regulation of context-dependent effector programs in Th17 and Treg cells

Gabele,

Sprang,

Cihan

et al. 2023

Preprint

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The transcription factor interferon regulatory factor 4 (IRF4) is crucial for the differentiation and fate determination of pro-inflammatory T helper (Th)17 and the functionally opposing group of immunomodulatory regulatory T (Treg) cells. However, molecular mechanisms of how IRF4 steers diverse transcriptional programs in Th17 and Treg cells are far from being definitive. To unveil IRF4-driven lineage determination in Th17 and Treg cells, we integrated data derived from affinity-purification and full mass spectrometry-based proteome analysis with chromatin immune precipitation sequencing (ChIP-Seq). This allowed the characterization of subtype-specific molecular programs and the identification of novel, previously unknown IRF4 interactors in the Th17/Treg context, such as RORγt, AHR, IRF8, BACH2, SATB1, and FLI1. Moreover, our data reveal that most of these transcription factors are recruited to IRF composite elements for the regulation of cell type-specific transcriptional programs providing a valuable resource for studying IRF4-mediated gene regulatory programs in pro- and anti-inflammatory immune responses.

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Section: Discussionsupporting

confidence: 91%

Unveiling IRF4-steered regulation of context-dependent effector programs in Th17 and Treg cells

Gabele,

Sprang,

Cihan

et al. 2023

Preprint

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“…Fli-1 promoted transcription of T-bet, RORγt in CD4 + T cells, but inhibited expression of activation-related genes and function-related genes within CD8 + T cells. 16 In bleomycin-treated Fli-1 +/− mice, the percentage of Treg cells from the dermis was decreased in relative to that in bleomycin-treated controls, but percentages of Th1, Th2, and Th17 cells did not markedly change between them. 12 Levels of GM-CSF was relatively low in Fli-1 +/− T cells, where Fli-1 directly binds to GM-CSF promoter.…”

Section: Impact Of Fli-1 On Immune Cellsmentioning

confidence: 83%

“…CD4 + Fli‐1 +/− T cells treated with Th1/Th17 polarizing‐conditions induced little proportion of Th1, Th17 cell. Fli‐1 promoted transcription of T‐bet, RORγt in CD4 + T cells, but inhibited expression of activation‐related genes and function‐related genes within CD8 + T cells 16 . In bleomycin‐treated Fli‐1 +/− mice, the percentage of Treg cells from the dermis was decreased in relative to that in bleomycin‐treated controls, but percentages of Th1, Th2, and Th17 cells did not markedly change between them 12 .…”

Section: Function Of Fli‐1 On Immune Cells and Non‐immune Cellsmentioning

confidence: 92%

Targeting Fli‐1 and chemokine axis CXCL10/CXCL13/CXCR3 in systemic lupus erythematosus and lupus nephritis

Zhu

2024

Int J of Rheum Dis

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Fli‐1 is a critical factor involved in hematopoietic stem cells, vascular endothelial cells apoptosis, and differentiation. Similarly, Fli‐1 regulates immune cell proliferation and differentiation, such as T cells, B cells, and monocytes. Regarding T/B cell dysfunction, SLE including LN is recognized to be associated with abnormal expression and function of Fli‐1. Moreover, three ligands of Fli‐1 including CXCL10 (C‐X‐C motif chemokine ligand 10), CXCR3 (C‐X‐C motif chemokine receptor 3), CXCL13 are widely discussed in SLE/LN. In this comprehensive review, we not only discussed Fli‐1 within SLE/LN pathogenesis, but also discussed the effects of CXCL10, CXCR3, and CXCL13 on SLE/LN development. Furthermore, we discussed how Fli‐1 regulates CXCL10, CXCR3, and CXCL13, and then involved in lupus development. It is possible that the Fli‐1 axis might be a potential target in SLE and LN.

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“…6 D). Moreover, T5224 significantly inhibited camptothecin (CPT, an anti-FLI1 compound [ 20 , 41 , 42 ])-induced HEL apoptosis in culture (Fig. 6 E, F).…”

Section: Resultsmentioning

confidence: 99%

FLI1 induces erythroleukemia through opposing effects on UBASH3A and UBASH3B expression

Wang,

et al. 2024

BMC Cancer

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Background FLI1 is an oncogenic transcription factor that promotes diverse malignancies through mechanisms that are not fully understood. Herein, FLI1 is shown to regulate the expression of Ubiquitin Associated and SH3 Domain Containing A/B (UBASH3A/B) genes. UBASH3B and UBASH3A are found to act as an oncogene and tumor suppressor, respectively, and their combined effect determines erythroleukemia progression downstream of FLI1. Methods Promoter analysis combined with luciferase assays and chromatin immunoprecipitation (ChIP) analysis were applied on the UBASH3A/B promoters. RNAseq analysis combined with bioinformatic was used to determine the effect of knocking-down UBASH3A and UBASH3B in leukemic cells. Downstream targets of UBASH3A/B were inhibited in leukemic cells either via lentivirus-shRNAs or small molecule inhibitors. Western blotting and RT-qPCR were used to determine transcription levels, MTT assays to assess proliferation rate, and flow cytometry to examine apoptotic index. Results Knockdown of FLI1 in erythroleukemic cells identified the UBASH3A/B genes as potential downstream targets. Herein, we show that FLI1 directly binds to the UBASH3B promoter, leading to its activation and leukemic cell proliferation. In contrast, FLI1 indirectly inhibits UBASH3A transcription via GATA2, thereby antagonizing leukemic growth. These results suggest oncogenic and tumor suppressor roles for UBASH3B and UBASH3A in erythroleukemia, respectively. Mechanistically, we show that UBASH3B indirectly inhibits AP1 (FOS and JUN) expression, and that its loss leads to inhibition of apoptosis and acceleration of proliferation. UBASH3B also positively regulates the SYK gene expression and its inhibition suppresses leukemia progression. High expression of UBASH3B in diverse tumors was associated with worse prognosis. In contrast, UBASH3A knockdown in erythroleukemic cells increased proliferation; and this was associated with a dramatic induction of the HSP70 gene, HSPA1B. Accordingly, knockdown of HSPA1B in erythroleukemia cells significantly accelerated leukemic cell proliferation. Accordingly, overexpression of UBASH3A in different cancers was predominantly associated with good prognosis. These results suggest for the first time that UBASH3A plays a tumor suppressor role in part through activation of HSPA1B. Conclusions FLI1 promotes erythroleukemia progression in part by modulating expression of the oncogenic UBASH3B and tumor suppressor UBASH3A.

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The druggable transcription factor Fli-1 regulates T cell immunity and tolerance in graft-versus-host disease

Abstract: Brief summary: Fli-1 regulates both inflammatory and anti-inflammatory T-cell subsets and can be targeted via available pharmaceutical agents.

Cited by 8 publications

References 71 publications

Unveiling IRF4-steered regulation of context-dependent effector programs in Th17 and Treg cells

Unveiling IRF4-steered regulation of context-dependent effector programs in Th17 and Treg cells

Targeting Fli‐1 and chemokine axis CXCL10/CXCL13/CXCR3 in systemic lupus erythematosus and lupus nephritis

FLI1 induces erythroleukemia through opposing effects on UBASH3A and UBASH3B expression

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