17 results found
Katsarou A, Trasanidis N, Ponnusamy K, et al., 2023, MAF functions as a pioneer transcription factor that initiates and sustains myelomagenesis., Blood Adv
Deregulated expression of lineage-affiliated transcription factors is a major mechanism of oncogenesis. However, how deregulation of non-lineage affiliated TF impacts chromatin to initiate oncogenic transcriptional programmes is not well known. To address this, we studied the chromatin effects imposed by oncogenic MAF as the cancer-initiating driver in the plasma cell cancer multiple myeloma. We found that the ectopically expressed MAF endows myeloma plasma cells with migratory and proliferative transcriptional potential. This potential is regulated by activation of enhancers and super-enhancers, previously inactive in normal B cells and plasma cells, and in co-operation of MAF with the plasma cell-defining TF IRF4. Forced ectopic MAF expression confirms the de novo ability of oncogenic MAF to convert transcriptionally inert chromatin to active chromatin with features of super-enhancers, leading to activation of the MAF-specific oncogenic transcriptome and acquisition of cancer-related cellular phenotypes such as CCR1-dependent cell migration. These findings establish oncogenic MAF as a pioneer transcription factor that can initiate as well as sustain oncogenic transcriptomes and cancer phenotypes. However, despite its pioneer function, myeloma cells remain MAF-dependent thus validating oncogenic MAF as a therapeutic target that would be able to circumvent the challenges of subsequent genetic diversification driving disease relapse and drug resistance.
Trasanidis N, Katsarou A, Ponnusamy K, et al., 2022, Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma, BLOOD, Vol: 139, Pages: 1939-1953, ISSN: 0006-4971
Thomsen I, Kunowska N, de Souza R, et al., 2021, RUNX1 regulates a transcription program that affects the dynamics of cell cycle entry of naive resting B cells, Journal of Immunology, Vol: 207, Pages: 2976-2991, ISSN: 0022-1767
RUNX1 is a transcription factor that plays key roles in hematopoietic development and in hematopoiesis and lymphopoiesis. In this article, we report that RUNX1 regulates a gene expression program in naive mouse B cells that affects the dynamics of cell cycle entry in response to stimulation of the BCR. Conditional knockout of Runx1 in mouse resting B cells resulted in accelerated entry into S-phase after BCR engagement. Our results indicate that Runx1 regulates the cyclin D2 (Ccnd2) gene, the immediate early genes Fosl2, Atf3, and Egr2, and the Notch pathway gene Rbpj in mouse B cells, reducing the rate at which transcription of these genes increases after BCR stimulation. RUNX1 interacts with the chromatin remodeler SNF-2-related CREB-binding protein activator protein (SRCAP), recruiting it to promoter and enhancer regions of the Ccnd2 gene. BCR-mediated activation triggers switching between binding of RUNX1 and its paralog RUNX3 and between SRCAP and the switch/SNF remodeling complex member BRG1. Binding of BRG1 is increased at the Ccnd2 and Rbpj promoters in the Runx1 knockout cells after BCR stimulation. We also find that RUNX1 exerts positive or negative effects on a number of genes that affect the activation response of mouse resting B cells. These include Cd22 and Bank1, which act as negative regulators of the BCR, and the IFN receptor subunit gene Ifnar1 The hyperresponsiveness of the Runx1 knockout B cells to BCR stimulation and its role in regulating genes that are associated with immune regulation suggest that RUNX1 could be involved in regulating B cell tolerance.
Sarkar M, Martufi M, Roman-Trufero M, et al., 2021, CNOT3 interacts with the Aurora B and MAPK/ERK kinases to promote survival of differentiating mesendodermal progenitor cells, Molecular Biology of the Cell, Vol: 32, ISSN: 1044-2030
Mesendoderm cells are key intermediate progenitors that form at the early primitive streak (PrS) and give rise to mesoderm and endoderm in the gastrulating embryo. We have identified an interaction between CNOT3 and the cell cycle kinase Aurora B that requires sequences in the NOT box domain of CNOT3 and regulates MAPK/ERK signaling during mesendoderm differentiation. Aurora B phosphorylates CNOT3 at two sites located close to a nuclear localization signal and promotes localization of CNOT3 to the nuclei of mouse embryonic stem cells (ESCs) and metastatic lung cancer cells. ESCs that have both sites mutated give rise to embryoid bodies that are largely devoid of mesoderm and endoderm and are composed mainly of cells with ectodermal characteristics. The mutant ESCs are also compromised in their ability to differentiate into mesendoderm in response to FGF2, BMP4, and Wnt3 due to reduced survival and proliferation of differentiating mesendoderm cells. We also show that the double mutation alters the balance of interaction of CNOT3 with Aurora B and with ERK and reduces phosphorylation of ERK in response to FGF2. Our results identify a potential adaptor function for CNOT3 that regulates the Ras/MEK/ERK pathway during embryogenesis.
Bond J, Domaschenz R, Roman-Trufero M, et al., 2016, Direct interaction of Ikaros and Foxp1 modulates expression of the G protein-coupled receptor G2A in B-lymphocytes and acute lymphoblastic leukemia, Oncotarget, Vol: 7, Pages: 65923-65936, ISSN: 1949-2553
Ikaros and Foxp1 are transcription factors that play key roles in normal lymphopoiesis and lymphoid malignancies. We describe a novel physical and functional interaction between the proteins, which requires the central zinc finger domain of Ikaros. The Ikaros-Foxp1 interaction is abolished by deletion of this region, which corresponds to the IK6 isoform that is commonly associated with high-risk acute lymphoblastic leukemia (ALL). We also identify the Gpr132 gene, which encodes the orphan G protein-coupled receptor G2A, as a novel target for Foxp1. Increased expression of Foxp1 enhanced Gpr132 transcription and caused cell cycle changes, including G2 arrest. Co-expression of wild-type Ikaros, but not IK6, displaced Foxp1 binding from the Gpr132 gene, reversed the increase in Gpr132 expression and inhibited G2 arrest. Analysis of primary ALL samples revealed a significant increase in GPR132 expression in IKZF1-deleted BCR-ABL negative patients, suggesting that levels of wild-type Ikaros may influence the regulation of G2A in B-ALL. Our results reveal a novel effect of Ikaros haploinsufficiency on Foxp1 functioning, and identify G2A as a potential modulator of the cell cycle in Ikaros-deleted B-ALL.
Sabbattini P, Sjoberg M, Nikic S, et al., 2014, An H3K9/S10 methyl-phospho switch modulates Polycomb and Pol II binding at repressed genes during differentiation, MOLECULAR BIOLOGY OF THE CELL, Vol: 25, Pages: 904-915, ISSN: 1059-1524
Auner HW, Beham-Schmid C, Dillon N, et al., 2010, The life span of short-lived plasma cells is partly determined by a block on activation of apoptotic caspases acting in combination with endoplasmic reticulum stress, BLOOD, Vol: 116, Pages: 3445-3455, ISSN: 0006-4971
Auner HW, Beham-Schmid C, Dillon N, et al., 2008, ER Stress and Inhibition of Key Apoptotic Caspases Regulate the Life Span of Short-Lived Plasma Cells., 50th Annual Meeting of the American-Society-of-Hematology, Publisher: AMER SOC HEMATOLOGY, Pages: 887-887, ISSN: 0006-4971
Sabbattini P, Canzonetta C, Sjoberg M, et al., 2007, Novel role for the Aurora B kinase in epigenetic marking of silent chromatin in differentiated postmitotic cells, EMBO JOURNAL, Vol: 26, Pages: 4657-4669, ISSN: 0261-4189
Thompson EC, Cobb BS, Sabbattini P, et al., 2007, Ikaros DNA-binding proteins as integral components of B cell developmental-stage-specific regulatory circuits., Immunity, Vol: 26, Pages: 335-344, ISSN: 1074-7613
Ikaros DNA-binding proteins are critical for the development of lymphocytes and other hematopoietic lineages, but it remains unclear how they cooperate with other regulators of signaling and transcription to achieve ordered gene expression during development. Here, we show that Ikaros proteins regulate the pre-BCR component lambda5 in a stage-specific manner. In pre-BI cells, Ikaros modulated lambda5 expression in competition with the transcriptional activator EBF. This required Ikaros binding to the Igll1 (lambda5) promoter and was abolished either by mutation of the Ikaros DNA-binding domain or by deletion of a single Ikaros site from the Igll1 promoter. At the transition from the pre-BI to pre-BII stage, the expression of the Ikaros family member Aiolos was upregulated and required for the efficient silencing of Igll1. Aiolos expression was controlled by pre-BCR signals via the adaptor protein SLP-65. Thus, pre-BCR signaling regulates Aiolos and the silencing of Igll1 via a developmental-stage-specific feedback loop.
Minaee S, Farmer D, Georgiou A, et al., 2005, Mapping and functional analysis of regulatory sequences in the mouse λ5-VpreB1 domain, MOLECULAR IMMUNOLOGY, Vol: 42, Pages: 1283-1292, ISSN: 0161-5890
Sabbattini P, Dillon N, 2005, The <i>λ5</i>-<i>VpreB1</i> locus -: a model system for studying gene regulation during early B cell development, SEMINARS IN IMMUNOLOGY, Vol: 17, Pages: 121-127, ISSN: 1044-5323
Sabbattini P, Lundgren M, Georgiou A, et al., 2001, Binding of Ikaros to the λ5 promoter silences transcription through a mechanism that does not require heterochromatin formation, EMBO JOURNAL, Vol: 20, Pages: 2812-2822, ISSN: 0261-4189
Lundgren M, Chow CM, Sabbattini P, et al., 2000, Transcription factor dosage affects changes in higher order chromatin structure associated with activation of a heterochromatic gene, CELL, Vol: 103, Pages: 733-743, ISSN: 0092-8674
Dillon N, Sabbattini P, 2000, Functional gene expression domains: defining the functional unit of eukaryotic gene regulation, BIOESSAYS, Vol: 22, Pages: 657-665, ISSN: 0265-9247
Sabbattini P, Georgiou A, Sinclair C, et al., 1999, Analysis of mice with single and multiple copies of transgenes reveals a novel arrangement for the <i>λ5-V</i><sub>preB1</sub> locus control region, MOLECULAR AND CELLULAR BIOLOGY, Vol: 19, Pages: 671-679, ISSN: 0270-7306
Sabbattini P, Six E, Zangrossi S, et al., 1996, Immunity specificity determinants in the P4-like retronphage phi R73, Virology, Vol: 216, Pages: 389-396
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