Person: George, Rani
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George
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Rani
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George, Rani
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Publication BORIS Promotes Chromatin Regulatory Interactions in Treatment-Resistant Cancer Cells(Springer Science and Business Media LLC, 2019-08) Dries, Ruben; Seruggia, Davide; Gao, Yang; Sharma, Bandana; Huang, Hao; Moreau, Lisa; McLane, Michael; Marco, Eugenio; Chen, Ting; Yuan, Guo-Cheng; Young, Richard A.; Debruyne, David; Day, Daniel; Gray, Nathanael; Wong, Kwok-Kin; Orkin, Stuart; George, Rani; Sengupta, SatyakiThe CCCTC-binding factor (CTCF), which anchors DNA loops that organize the genome into structural domains, plays a central role in gene control by facilitating or constraining interactions between genes and their regulatory elements. In cancer cells the disruption of CTCF binding at specific loci through somatic mutation or DNA hypermethylation5 results in the loss of loop anchors and consequent activation of oncogenes. By contrast, the germ cell-specific paralog of CTCF, BORIS (Brother of the Regulator of Imprinted Sites), is overexpressed in multiple cancers, but its contributions to the malignant phenotype remain unclear. Here we show that aberrant upregulation of BORIS promotes novel chromatin interactions in ALK-mutated, MYCN-amplified neuroblastoma cells rendered resistant to ALK inhibition. These cells are reprogrammed to a distinct phenotypic state during the acquisition of resistance, a process defined by the initial loss of MYCN expression followed by subsequent overexpression of BORIS and a concomitant switch in cellular dependence from MYCN to BORIS. The resultant BORIS-regulated alterations in chromatin looping lead to the formation of new super-enhancers that drive the ectopic expression of a subset of proneural transcription factors that ultimately define the resistance phenotype. These results identify a previously unrecognized role of BORIS – to engender regulatory chromatin interactions that support specific cancer phenotypes.Publication Cbx3/HP1γ deficiency confers enhanced tumor-killing capacity on CD8+ T cells(Nature Publishing Group, 2017) Sun, Michael; Ha, Ngoc; Pham, Duc-Hung; Frederick, Megan; Sharma, Bandana; Naruse, Chie; Asano, Masahide; Pipkin, Matthew E.; George, Rani; Thai, To-HaCbx3/HP1γ is a histone reader whose function in the immune system is not completely understood. Here, we demonstrate that in CD8+ T cells, Cbx3/HP1γ insufficiency leads to chromatin remodeling accompanied by enhanced Prf1, Gzmb and Ifng expression. In tumors obtained from Cbx3/HP1γ-insufficient mice or wild type mice treated with Cbx3/HP1γ-insufficient CD8+ T cells, there is an increase of CD8+ effector T cells expressing the stimulatory receptor Klrk1/NKG2D, a decrease in CD4+ CD25+ FOXP3+ regulatory T cells (Treg cells) as well as CD25+ CD4+ T cells expressing the inhibitory receptor CTLA4. Together these changes in the tumor immune environment may have mitigated tumor burden in Cbx3/HP1γ-insufficient mice or wild type mice treated with Cbx3/HP1γ-insufficient CD8+ T cells. These findings suggest that targeting Cbx3/HP1γ can represent a rational therapeutic approach to control growth of solid tumors.Publication Intrinsic Susceptibility MRI Identifies Tumors with ALKF1174L Mutation in Genetically-Engineered Murine Models of High-Risk Neuroblastoma(Public Library of Science, 2014) Jamin, Yann; Glass, Laura; Hallsworth, Albert; George, Rani; Koh, Dow-Mu; Pearson, Andrew D. J.; Chesler, Louis; Robinson, Simon P.The early identification of children presenting ALKF1174L-mutated neuroblastoma, which are associated with resistance to the promising ALK inhibitor crizotinib and a marked poorer prognosis, has become a clinical priority. In comparing the radiology of the novel Th-ALKF1174L/Th-MYCN and the well-established Th-MYCN genetically-engineered murine models of neuroblastoma using MRI, we have identified a marked ALKF1174L-driven vascular phenotype. We demonstrate that quantitation of the transverse relaxation rate R2* (s−1) using intrinsic susceptibility-MRI under baseline conditions and during hyperoxia, can robustly discriminate this differential vascular phenotype, and identify MYCN-driven tumors harboring the ALKF1174L mutation with high specificity and selectivity. Intrinsic susceptibility-MRI could thus potentially provide a non-invasive and clinically-exploitable method to help identifying children with MYCN-driven neuroblastoma harboring the ALKF1174L mutation at the time of diagnosis.Publication Distinct Neuroblastoma-associated Alterations of PHOX2B Impair Sympathetic Neuronal Differentiation in Zebrafish Models(Public Library of Science, 2013) Pei, Desheng; Luther, William; Wang, Wenchao; Paw, Barry Htin; Stewart, Rodney A.; George, RaniHeterozygous germline mutations and deletions in PHOX2B, a key regulator of autonomic neuron development, predispose to neuroblastoma, a tumor of the peripheral sympathetic nervous system. To gain insight into the oncogenic mechanisms engaged by these changes, we used zebrafish models to study the functional consequences of aberrant PHOX2B expression in the cells of the developing sympathetic nervous system. Allelic deficiency, modeled by phox2b morpholino knockdown, led to a decrease in the terminal differentiation markers th and dbh in sympathetic ganglion cells. The same effect was seen on overexpression of two distinct neuroblastoma-associated frameshift mutations, 676delG and K155X - but not the R100L missense mutation - in the presence of endogenous Phox2b, pointing to their dominant-negative effects. We demonstrate that Phox2b is capable of regulating itself as well as ascl1, and that phox2b deficiency uncouples this autoregulatory mechanism, leading to inhibition of sympathetic neuron differentiation. This effect on terminal differentiation is associated with an increased number of phox2b+, ascl1+, elavl3− cells that respond poorly to retinoic acid. These findings suggest that a reduced dosage of PHOX2B during development, through either a heterozygous deletion or dominant-negative mutation, imposes a block in the differentiation of sympathetic neuronal precursors, resulting in a cell population that is likely to be susceptible to secondary transforming events.Publication Genome-Wide Analysis of Neuroblastomas using High-Density Single Nucleotide Polymorphism Arrays(Public Library of Science, 2007) Attiyeh, Edward F.; Moreau, Lisa A.; Fortina, Paolo; Maris, John M.; George, Rani; Li, Shuli; Neuberg, Donna; Li, Cheng; Fox, Edward Alvin; Meyerson, Matthew; Diller, Lisa; Look, A.Background: Neuroblastomas are characterized by chromosomal alterations with biological and clinical significance. We analyzed paired blood and primary tumor samples from 22 children with high-risk neuroblastoma for loss of heterozygosity (LOH) and DNA copy number change using the Affymetrix 10K single nucleotide polymorphism (SNP) array. Findings: Multiple areas of LOH and copy number gain were seen. The most commonly observed area of LOH was on chromosome arm 11q (15/22 samples; 68%). Chromosome 11q LOH was highly associated with occurrence of chromosome 3p LOH: 9 of the 15 samples with 11q LOH had concomitant 3p LOH (P = 0.016). Chromosome 1p LOH was seen in one-third of cases. LOH events on chromosomes 11q and 1p were generally accompanied by copy number loss, indicating hemizygous deletion within these regions. The one exception was on chromosome 11p, where LOH in all four cases was accompanied by normal copy number or diploidy, implying uniparental disomy. Gain of copy number was most frequently observed on chromosome arm 17q (21/22 samples; 95%) and was associated with allelic imbalance in six samples. Amplification of MYCN was also noted, and also amplification of a second gene, ALK, in a single case. Conclusions: This analysis demonstrates the power of SNP arrays for high-resolution determination of LOH and DNA copy number change in neuroblastoma, a tumor in which specific allelic changes drive clinical outcome and selection of therapy.Publication Discovery of 3,5-Diamino-1,2,4-triazole Ureas as Potent Anaplastic Lymphoma Kinase Inhibitors(American Chemical Society, 2011) Deng, Xianming; Wang, Jinhua; Zhang, Jianming; Sim, Taebo; Kim, Nam Doo; Sasaki, Takaaki; Luther, William; George, Rani; Jänne, Pasi A.; Gray, NathanaelA series of novel 3,5-diamino-1,2,4-triazole benzyl ureas was identified as having potent anaplastic lymphoma kinase (ALK) inhibition exemplified by 15a, 20a, and 23a, which exhibited antiproliferative IC50 values of 70, 40, and 20 nM in Tel-ALK transformed Ba/F3 cells, respectively. Moreover, 15a and 23a potently inhibited the growth and survival of NPM-ALK positive anaplastic large cell lymphoma cell (SU-DHL-1) and neuroblastoma cell lines (KELLY, SH-SY5Y) containing the F1174L ALK mutation. These compounds provide novel leads for the development of small-molecule ALK inhibitors for cancer therapy.