Direct interaction of Ikaros and Foxp1 modulates expression of the G protein-coupled receptor G2A in B-lymphocytes and acute lymphoblastic leukemia

Bond, Jonathan; Domaschenz, Renae; Román-Trufero, Mónica; Sabbattini, Pierangela; Ferreirós-Vidal, Isabel; Gerrard, Gareth; Asnafi, Vahid; Macintyre, Elizabeth; Merkenschlager, Matthias; Dillon, Niall

doi:10.18632/oncotarget.11688

Cited by 9 publications

(10 citation statements)

References 48 publications

(52 reference statements)

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“…2a) including canonical plasma and memory cell differentiation genes such as Irf4 and Prdm1, as well as Cd80, which is important for B cell induction of follicular helper T (T FH ) cells 17 , Cxcr3, which plays a critical role in plasma cell differentiation 18 and Stat4, which induces plasma cell differentiation in GC B cells downstream of IL-12 19 . Lsd1 loss of function also yielded upregulation of Gpr132 , a gene that suppresses the proliferation of B cells 20 .…”

Section: Resultsmentioning

confidence: 99%

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Histone demethylase LSD1 is required for germinal center formation and BCL6-driven lymphomagenesis

et al. 2018

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Germinal center (GC) B cells feature repression of many gene enhancers to establish their characteristic transcriptome. Here we show that conditional deletion of Lsd1 in GCs significantly impaired GC formation, associated with to failure to repress immune synapse genes linked to GC exit, which are also direct targets of the BCL6 transcriptional repressor. We found that BCL6 directly binds and recruits LSD1, primarily to intergenic and intronic enhancers. Conditional deletion of Lsd1 suppressed GC hyperplasia caused by constitutive expression of Bcl6, and significantly delayed Bcl6-driven lymphomagenesis. Administration of LSD1 catalytic inhibitors had little effect on GC formation or GC derived lymphoma cells. Using a CRISPR/Cas9 domain screen we found instead that the LSD1 Tower domain was critical for LSD1 dependency in GC derived B cells. These results indicate an essential role of LSD1 in the humoral immune response, where it modulates enhancer function by forming repression complexes with BCL6.

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Section: Resultsmentioning

confidence: 99%

“…Failure to proliferate could also be linked to upregulation of genes that inhibit cell cycle progression. One of these genes, the orphan G-coupled receptor Gpr132 was shown to arrest cell cycle progression in B cells downstream of IKZF 20 .…”

Section: Discussionmentioning

confidence: 99%

Histone demethylase LSD1 is required for germinal center formation and BCL6-driven lymphomagenesis

et al. 2018

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“…Knockout mouse models have established a putative tumor suppressive role of GPR132 in leukemia and analysis of primary leukemic samples has revealed high GPR132 expression [123] , [126] . High GPR132 expression is inconsistent with a tumor suppressor role and may not necessarily be associated with functional activation.…”

Section: Imipridone Chemical Scaffold and Onc201 Analogsmentioning

confidence: 99%

ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

et al. 2020

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ONC201 was originally discovered as TNF-Related Apoptosis Inducing Ligand (TRAIL)-inducing compound TIC10. ONC201 appears to act as a selective antagonist of the G protein coupled receptor (GPCR) dopamine receptor D2 (DRD2), and as an allosteric agonist of mitochondrial protease caseinolytic protease P (ClpP). Downstream of target engagement, ONC201 activates the ATF4/CHOP-mediated integrated stress response leading to TRAIL/Death Receptor 5 (DR5) activation, inhibits oxidative phosphorylation via c-myc, and inactivates Akt/ERK signaling in tumor cells. This typically results in DR5/TRAIL-mediated apoptosis of tumor cells; however, DR5/TRAIL-independent apoptosis, cell cycle arrest, or antiproliferative effects also occur. The effects of ONC201 extend beyond bulk tumor cells to include cancer stem cells, cancer associated fibroblasts and immune cells within the tumor microenvironment that can contribute to its efficacy. ONC201 is orally administered, crosses the intact blood brain barrier, and is under evaluation in clinical trials in patients with advanced solid tumors and hematological malignancies. ONC201 has single agent clinical activity in tumor types that are enriched for DRD2 and/or ClpP expression including specific subtypes of high-grade glioma, endometrial cancer, prostate cancer, mantle cell lymphoma, and adrenal tumors. Synergy with radiation, chemotherapy, targeted therapy and immune-checkpoint agents has been identified in preclinical models and is being evaluated in clinical trials. Structure-activity relationships based on the core pharmacophore of ONC201, termed the imipridone scaffold, revealed novel potent compounds that are being developed. Imipridones represent a novel approach to therapeutically target previously undruggable GPCRs, ClpP, and innate immune pathways in oncology.

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“…Initially characterized by germline deletion, in this study, we identified FOXP1 loss in the mouse as a requirement for pro-B to pre-B cell transition. In humans, this transition is often breached in acute lymphocytic leukemia, and FOXP1 loss or gain has been the culprit in several cases (19,(96)(97)(98). FOXP1 has been recognized as an oncogene in various mature B cell tumors, such as non-Hodgkin lymphomas (24,99).…”

Section: Convergent Analyses Of Foxp1 B Cell Biologymentioning

confidence: 99%

Loss of the FOXP1 Transcription Factor Leads to Deregulation of B Lymphocyte Development and Function at Multiple Stages

et al. 2019

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The FOXP1 transcription factor is expressed throughout B cell development until its extinction just prior to terminal differentiation. Foxp1 nulls die of cardiac defects at midgestation, but adult rescue via fetal liver transfer led to a strong pre-B cell block. To circumvent these limitations and to investigate FOXP1 function at later stages of B cell differentiation, we generated and analyzed floxed (F) Foxp1 alleles deleted at pro-B, transitional (T) 1, and mature B cell stages. Mb-1cre-mediated deletion of Foxp1 F/F confirmed its requirement for pro-B to pre-B transition. Cd21-and Cd19cre deletion led to significant reduction of germinal center formation and a second block in differentiation at the T2/marginal zone precursor stage. T-dependent and-independent immunization of FOXP1 mutants led to reduction of Ag-specific IgM, whereas responses of class-switched Abs were unimpaired. Yet, unexpectedly, plasmablast and plasma cell numbers were significantly increased by in vitro BCR stimulation of Foxp1 F/F splenic follicular B cells but rapidly lost, as they were highly prone to apoptosis. RNA sequencing, gene set enrichment analysis, and chromatin immunoprecipitation sequencing analyses revealed strong enrichment for signatures related to downregulation of immune responses, apoptosis, and germinal center biology, including direct activation of Bcl6 and downregulation of Aicda/AID, the primary effector of somatic hypermutation, and class-switch recombination. These observations support a role for FOXP1 as a direct transcriptional regulator at key steps underlying B cell development in the mouse. ImmunoHorizons, 2019, 3: 447-462.

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Direct interaction of Ikaros and Foxp1 modulates expression of the G protein-coupled receptor G2A in B-lymphocytes and acute lymphoblastic leukemia

Cited by 9 publications

References 48 publications

Histone demethylase LSD1 is required for germinal center formation and BCL6-driven lymphomagenesis

Histone demethylase LSD1 is required for germinal center formation and BCL6-driven lymphomagenesis

ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

Loss of the FOXP1 Transcription Factor Leads to Deregulation of B Lymphocyte Development and Function at Multiple Stages

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