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Beate Heizmann, Philippe Kastner, Susan Chan
The IKZF family of transcription factors are essential regulators of lymphopoiesis. Ikaros, Helios, Aiolos and Eos function as transcriptional repressors and activators during T and B cell differentiation and in mature cell function, depending on the stage of development and/or cell type. Their potential mechanisms of action are varied. Ikaros family proteins partner with multiple complexes, including NuRD, PRC2 and transcription elongation factors, to modulate gene expression and the chromatin state. In humans, mutations in the IKZF genes are associated with B cell deficiency, leukemias and autoimmunity...
December 23, 2017: Current Opinion in Immunology
Li Yin, Ashujit Tagde, Reddy Gali, Yu-Tzu Tai, Teru Hideshima, Kenneth Anderson, David Avigan, Donald Kufe
Lenalidomide (LEN) acts directly on multiple myeloma (MM) cells by inducing cereblon-mediated degradation of interferon regulatory factor 4, Ikaros (IKZF)1 and IKZF3, transcription factors that are essential for MM cell survival. The mucin 1 (MUC1) C-terminal transmembrane subunit (MUC1-C) oncoprotein is aberrantly expressed by MM cells and protects against reactive oxygen species (ROS)-mediated MM cell death. The present studies demonstrate that targeting MUC1-C with GO-203, a cell-penetrating peptide inhibitor of MUC1-C homodimerization, is more than additive with LEN in downregulating the WNT/β-catenin pathway, suppressing MYC, and inducing late apoptosis/necrosis...
September 2017: British Journal of Haematology
Ashley J Waardenberg, Bernou Homan, Stephanie Mohamed, Richard P Harvey, Romaric Bouveret
The ability to accurately predict the DNA targets and interacting cofactors of transcriptional regulators from genome-wide data can significantly advance our understanding of gene regulatory networks. NKX2-5 is a homeodomain transcription factor that sits high in the cardiac gene regulatory network and is essential for normal heart development. We previously identified genomic targets for NKX2-5 in mouse HL-1 atrial cardiomyocytes using DNA-adenine methyltransferase identification (DamID). Here, we apply machine learning algorithms and propose a knowledge-based feature selection method for predicting NKX2-5 protein : protein interactions based on motif grammar in genome-wide DNA-binding data...
September 2016: Open Biology
K Polgárová, M Vášková, E Froňková, L Slámová, T Kalina, E Mejstříková, A Dobiášová, K Fišer, O Hrušák
Differentiation during hematopoiesis leads to the generation of many cell types with specific functions. At various stages of maturation, the cells may change pathologically, leading to diseases including acute leukemias (ALs). Expression levels of regulatory molecules (such as the IKZF, GATA, HOX, FOX, NOTCH and CEBP families, as well as SPI-1/PU1 and PAX5) and lineage-specific molecules (including CD2, CD14, CD79A, and BLNK) may be compared between pathological and physiological cells. Although the key steps of differentiation are known, the available databases focus mainly on fully differentiated cells as a reference...
January 2016: Differentiation; Research in Biological Diversity
Cinzia Fionda, Maria Pia Abruzzese, Alessandra Zingoni, Francesca Cecere, Elisabetta Vulpis, Giovanna Peruzzi, Alessandra Soriani, Rosa Molfetta, Rossella Paolini, Maria Rosaria Ricciardi, Maria Teresa Petrucci, Angela Santoni, Marco Cippitelli
Immunomodulatory drugs (IMiDs) have potent anti-tumor activities in multiple myeloma (MM) and are able to enhance the cytotoxic function of natural killer (NK) cells, important effectors of the immune response against MM. Here, we show that these drugs can enhance the expression of the NKG2D and DNAM-1 activating receptor ligands MICA and PVR/CD155 in human MM cell lines and primary malignant plasma cells. Depletion of cereblon (CRBN) by shRNA interference strongly impaired upregulation of these ligands and, more interestingly, IMiDs/CRBN-mediated downregulation of the transcription factors Ikaros (IKZF1), Aiolos (IKZF3) and IRF4 was critical for these regulatory mechanisms...
September 15, 2015: Oncotarget
Nicholas A Vitanza, Wafik Zaky, Roy Blum, Julia A Meyer, Jinhua Wang, Teena Bhatla, Debra J Morrison, Elizabeth A Raetz, William L Carroll
BACKGROUND: Ikaros, the product of IKZF1, is a regulator of lymphoid development and polymorphisms in the gene have been associated with the acute lymphoblastic leukemia (ALL). Additionally, IKZF1 deletions and mutations identify high-risk biological subsets of childhood ALL [Georgopoulos et al. Cell 1995;83(2):289-299; Mullighan et al. N Engl J Md 2009;360(5):470-480]. PROCEDURES: To discover the underlying pathways modulated by Ikaros we performed gene expression and gene ontology analysis in IKZF1 deleted primary B-ALL pediatric patient samples...
October 2014: Pediatric Blood & Cancer
Yuan Xiao Zhu, Esteban Braggio, Chang-Xin Shi, K Martin Kortuem, Laura A Bruins, Jessica E Schmidt, Xiu-Bao Chang, Paul Langlais, Moulun Luo, Patrick Jedlowski, Betsy LaPlant, Kristina Laumann, Rafael Fonseca, P Leif Bergsagel, Joseph Mikhael, Martha Lacy, Mia D Champion, A Keith Stewart
Cereblon (CRBN) mediates immunomodulatory drug (IMiD) action in multiple myeloma (MM). Using 2 different methodologies, we identified 244 CRBN binding proteins and established relevance to MM biology by changes in their abundance after exposure to lenalidomide. Proteins most reproducibly binding CRBN (>fourfold vs controls) included DDB1, CUL4A, IKZF1, KPNA2, LTF, PFKL, PRKAR2A, RANGAP1, and SHMT2. After lenalidomide treatment, the abundance of 46 CRBN binding proteins decreased. We focused attention on 2 of these-IKZF1 and IKZF3...
July 24, 2014: Blood
Gabriela Soriano, Mark Heaney
PURPOSE OF REVIEW: This review summarizes current understanding of the molecular genetics of polycythemia vera and essential thrombocythemia, with an emphasis on JAK2V617F pathophysiology and effect on disease phenotype. RECENT FINDINGS: JAK2V617F exerts its effects on cell growth via janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling and interactions with other molecules that normally negatively regulate signalling, such as suppressor of cell signalling 3...
March 2013: Current Opinion in Hematology
Hiromitsu Komiyama, Aya Aoki, Shigekazu Tanaka, Hiroshi Maekawa, Yoriko Kato, Ryo Wada, Takeo Maekawa, Masaru Tamura, Toshihiko Shiroishi
GASDERMIN B (GSDMB) belongs to the novel gene family GASDERMIN (GSDM). All GSDM family members are located in amplicons, genomic regions often amplified during cancer development. Given that GSDMB is highly expressed in cancerous cells and the locus resides in an amplicon, GSDMB may be involved in cancer development and/or progression. However, only limited information is available on GSDMB expression in tissues, normal and cancerous, from cancer patients. Furthermore, the molecular mechanisms that regulate GSDMB expression in gastric tissues are poorly understood...
February 2010: Genes & Genetic Systems
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