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Vasiliki Leventaki, Timothy Shaw, Stanley Pounds, Xueyuan Cao, Jing Ma, Gustavo Palacios, John Mason, Sherrie Perkins, Gang Wu, Yiping Fan, Jian Wang, Xin Zhou, Alyssa Obermayer, Marsha Kinney, Jacqueline Kraveka, Thomas Gross, John Sandlund, Jinghui Zhang, Charles Mullighan, Megan Lim
Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that accounts for for 10-15% of childhood lymphomas. Despite the observation that more than 90% of pediatric cases harbor the anaplastic lymphoma kinase (ALK) rearrangement resulting in aberrant ALK kinase expression, there is significant clinical, morphologic, and biological heterogeneity. To gain insights into the genomic aberrations and molecular heterogeneity within ALK-positive ALCL(ALK+ ALCL), we analyzed 46 pediatric ALK+ ALCLs by whole-exome sequencing, RNA-sequencing, and DNA methylation profiling...
March 28, 2024: Research Square
#2
REVIEW
Joanna E Zawacka
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) originate from preleukemic hematopoietic conditions, such as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenia of undetermined significance (CCUS) and have variable outcomes despite the successful implementation of targeted therapies. The prognosis differs depending on the molecular subgroup. In patients with TP53 mutations, the most inferior outcomes across independent studies were observed. Myeloid malignancies with TP53 mutations have complex cytogenetics and extensive structural variants...
March 13, 2024: Biomarker Research
#3
Hannah N W Weinstein, Kevin Hu, Lisa Fish, Yih-An Chen, Paul Allegakoen, Keliana S F Hui, Julia H Pham, Maria B Baco, Hanbing Song, Andrew O Giacomelli, Francisca Vazquez, Mahmoud Ghandi, Hani Goodarzi, Franklin W Huang
Microsatellite instability high (MSI-H) tumors are malignant tumors that, despite harboring a high mutational burden, often have intact TP53 . One of the most frequent mutations in MSI-H tumors is a frameshift mutation in RPL22 , a ribosomal protein. Here, we identified RPL22 as a modulator of MDM4 splicing through an alternative splicing switch in exon 6. RPL22 loss increases MDM4 exon 6 inclusion, cell proliferation, and augments resistance to the MDM inhibitor Nutlin-3a. RPL22 represses expression of its paralog, RPL22L1, by mediating the splicing of a cryptic exon corresponding to a truncated transcript...
December 10, 2023: bioRxiv
#4
Duna Barakeh, Afaf Alsolami, Malak Abedalthagafi
Ameloblastic fibrosarcoma (AFS) is considered a malignant progression resulting from dysplastic changes in an ameloblastic fibroma (AF). Both tumors are extremely rare, with only a few cases reported in the scientific literature. Notably, BRAF mutations have been identified in ameloblastomas, suggesting a connection between ameloblastic morphology and BRAF mutations, as AF is believed to be the precursor neoplasm leading to AFS. In this study, we present a case of AFS in a 25-year-old male. The tumor tissue underwent molecular analysis, specifically next-generation sequencing (NGS) using the Oncomine Comprehensive Assay v3 System...
2023: Case Reports in Oncology
#5
REVIEW
Jeanne Rakotopare, Franck Toledo
Mice with a constitutive increase in p53 activity exhibited features of dyskeratosis congenita (DC), a bone marrow failure syndrome (BMFS) caused by defective telomere maintenance. Further studies confirmed, in humans and mice, that germline mutations affecting TP53 or its regulator MDM4 may cause short telomeres and alter hematopoiesis, but also revealed features of Diamond-Blackfan anemia (DBA) or Fanconi anemia (FA), two BMFSs, respectively, caused by defects in ribosomal function or DNA repair. p53 downregulates several genes mutated in DC, either by binding to promoter sequences ( DKC1 ) or indirectly via the DREAM repressor complex ( RTEL1 , DCLRE1B ), and the p53-DREAM pathway represses 22 additional telomere-related genes...
October 6, 2023: International Journal of Molecular Sciences
#6
JOURNAL ARTICLE
Luca Gasparoli, Clemence Virely, Alexia Tsakaneli, Noelia Che, Darren Edwards, Jack Bartram, Michael Hubank, Deepali Pal, Olaf Heidenreich, Joost H A Martens, Jasper De Boer, Owen Williams
Advances in the clinical management of pediatric B cell Acute Lymphoblastic Leukemia (B-ALL) have dramatically improved outcomes for this disease. However, relapsed and high-risk disease still contribute to significant numbers of treatment failures. Development of new, broad range therapies is urgently needed for these cases. We previously reported the susceptibility of ETV6-RUNX1+ pediatric B-ALL to inhibition of signal transducer and activator of transcription 3 (STAT3) activity. In the present study, we demonstrate that pharmacological or genetic inhibition of STAT3 results in p53 induction and that CRISPR-mediated TP53 knockout substantially reverses susceptibility to STAT3 inhibition...
October 5, 2023: Haematologica
#7
JOURNAL ARTICLE
Safir Ullah Khan, Zahid Ullah, Hadia Shaukat, Sheeza Unab, Saba Jannat, Waqar Ali, Amir Ali, Muhammad Irfan, Muhammad Fiaz Khan, Rodolfo Daniel Cervantes-Villagrana
The present study was the first comprehensive investigation of genetic mutation and expression levels of the p53 signaling genes in cutaneous melanoma through various genetic databases providing large datasets. The mutational landscape of p53 and its signaling genes was higher than expected, with TP53 followed by CDKN2A being the most mutated gene in cutaneous melanoma. Furthermore, the expression analysis showed that TP53 , MDM2 , CDKN2A , and TP53BP1 were overexpressed, while MDM4 and CDKN2B were under-expressed in cutaneous melanoma...
2023: Cancer Informatics
#8
JOURNAL ARTICLE
Vincent Guerlavais, Tomi K Sawyer, Luis Carvajal, Yong S Chang, Bradford Graves, Jian-Guo Ren, David Sutton, Karen A Olson, Kathryn Packman, Krzysztof Darlak, Carl Elkin, Eric Feyfant, Kamala Kesavan, Pranoti Gangurde, Lyubomir T Vassilev, Huw M Nash, Vojislav Vukovic, Manuel Aivado, D Allen Annis
We report the discovery of sulanemadlin (ALRN-6924), the first cell-permeating, stabilized α-helical peptide to enter clinical trials. ALRN-6924 is a "stapled peptide" that mimics the N-terminal domain of the p53 tumor suppressor protein. It binds with high affinity to both MDM2 and MDMX (also known as MDM4), the endogenous inhibitors of p53, to activate p53 signaling in cells having a non-mutant, or wild-type TP53 genotype ( TP53 -WT). Iterative structure-activity optimization endowed ALRN-6924 with favorable cell permeability, solubility, and pharmacokinetic and safety profiles...
July 13, 2023: Journal of Medicinal Chemistry
#9
JOURNAL ARTICLE
Vishruth Girish, Asad A Lakhani, Sarah L Thompson, Christine M Scaduto, Leanne M Brown, Ryan A Hagenson, Erin L Sausville, Brianna E Mendelson, Pranav K Kandikuppa, Devon A Lukow, Monet Lou Yuan, Eric C Stevens, Sophia N Lee, Klaske M Schukken, Saron M Akalu, Anand Vasudevan, Charles Zou, Barbora Salovska, Wenxue Li, Joan C Smith, Alison M Taylor, Robert A Martienssen, Yansheng Liu, Ruping Sun, Jason M Sheltzer
Most cancers exhibit aneuploidy, but its functional significance in tumor development is controversial. Here, we describe ReDACT (Restoring Disomy in Aneuploid cells using CRISPR Targeting), a set of chromosome engineering tools that allow us to eliminate specific aneuploidies from cancer genomes. Using ReDACT, we created a panel of isogenic cells that have or lack common aneuploidies, and we demonstrate that trisomy of chromosome 1q is required for malignant growth in cancers harboring this alteration. Mechanistically, gaining chromosome 1q increases the expression of MDM4 and suppresses p53 signaling, and we show that TP53 mutations are mutually exclusive with 1q aneuploidy in human cancers...
August 25, 2023: Science
#10
JOURNAL ARTICLE
Bruno Fito-Lopez, Marina Salvadores, Miguel-Martin Alvarez, Fran Supek
BACKGROUND: TP53 is a master tumor suppressor gene, mutated in approximately half of all human cancers. Given the many regulatory roles of the corresponding p53 protein, it is possible to infer loss of p53 activity - which may occur due to alterations in trans - from gene expression patterns. Several such alterations that phenocopy p53 loss are known, however additional ones may exist, but their identity and prevalence among human tumors are not well characterized. RESULTS: We perform a large-scale statistical analysis on transcriptomes of ~ 7,000 tumors and ~ 1,000 cell lines, estimating that 12% and 8% of tumors and cancer cell lines, respectively, phenocopy TP53 loss: they are likely deficient in the activity of the p53 pathway, while not bearing obvious TP53 inactivating mutations...
April 24, 2023: BMC Biology
#11
REVIEW
Savitha Balachandran, Aru Narendran
Tumorigenesis, which involves the uncontrolled proliferation and differentiation of cells, has been observed to imitate a variety of pathways vital to embryonic development, motivating cancer researchers to explore the genetic origins of these pathways. The pluripotency gene regulatory network is an established collection of genes that induces stemness in embryonic cells. Dysregulation in the expression genes of the pluripotency gene networks including OCT4 , SOX2 , NANOG and REX1 have been implicated in tumor development, and have been observed to result in poorer patient outcomes...
February 28, 2023: Genes
#12
JOURNAL ARTICLE
Vivek Kumar, Archana Pandey, Arisha Arora, Priyanka Gautam, Deepa Bisht, Sameer Gupta, Amrita Chaurasia, Manisha Sachan
Epithelial ovarian cancer (EOC) treatment strategies mainly focused on surgery combined with chemotherapy. Recent targeted therapy techniques emerge as milestone and could be used for management of ovarian cancer (OC) progression with more efficacy. The aim is to evaluate the therapeutic and diagnostic potential of microRNA (miRNA) in management of EOC using in silico and quantitative real-time PCR (qRT-PCR) expression analysis. We performed functional enrichment and miRNA-Target genes expression analysis in 48 EOC and 22 normal tissue samples using qRT-PCR and correlated with miRNA expression data in matched samples to evaluate the diagnostic and therapeutic potential of miRNA in OC management...
February 13, 2023: DNA and Cell Biology
#13
JOURNAL ARTICLE
Marie Sebert, Stéphanie Gachet, Thierry Leblanc, Alix Rousseau, Olivier Bluteau, Rathana Kim, Raouf Ben Abdelali, Flore Sicre de Fontbrune, Loïc Maillard, Carèle Fedronie, Valentine Murigneux, Léa Bellenger, Naira Naouar, Samuel Quentin, Lucie Hernandez, Nadia Vasquez, Mélanie Da Costa, Pedro H Prata, Lise Larcher, Marie de Tersant, Matthieu Duchmann, Anna Raimbault, Franck Trimoreau, Odile Fenneteau, Wendy Cuccuini, Nathalie Gachard, Nathalie Auger, Giulia Tueur, Maud Blanluet, Claude Gazin, Michèle Souyri, Francina Langa Vives, Aaron Mendez-Bermudez, Hélène Lapillonne, Etienne Lengline, Emmanuel Raffoux, Pierre Fenaux, Lionel Adès, Edouard Forcade, Charlotte Jubert, Carine Domenech, Marion Strullu, Bénédicte Bruno, Nimrod Buchbinder, Caroline Thomas, Arnaud Petit, Guy Leverger, Gérard Michel, Marina Cavazzana, Eliane Gluckman, Yves Bertrand, Nicolas Boissel, André Baruchel, Jean-Hugues Dalle, Emmanuelle Clappier, Eric Gilson, Ludovic Deriano, Sylvie Chevret, François Sigaux, Gérard Socié, Dominique Stoppa-Lyonnet, Hugues de Thé, Christophe Antoniewski, Dominique Bluteau, Régis Peffault de Latour, Jean Soulier
Fanconi anemia (FA) patients experience chromosome instability, yielding hematopoietic stem/progenitor cell (HSPC) exhaustion and predisposition to poor-prognosis myeloid leukemia. Based on a longitudinal cohort of 335 patients, we performed clinical, genomic, and functional studies in 62 patients with clonal evolution. We found a unique pattern of somatic structural variants and mutations that shares features of BRCA-related cancers, the FA-hallmark being unbalanced, microhomology-mediated translocations driving copy-number alterations...
February 2, 2023: Cell Stem Cell
#14
Vishruth Girish, Asad A Lakhani, Christine M Scaduto, Sarah L Thompson, Leanne M Brown, Ryan A Hagenson, Erin L Sausville, Brianna E Mendelson, Devon A Lukow, Monet Lou Yuan, Pranav K Kandikuppa, Eric C Stevens, Sophia N Lee, Barbora Salovska, Wenxue Li, Joan C Smith, Alison M Taylor, Robert A Martienssen, Yansheng Liu, Ruping Sun, Jason M Sheltzer
Most cancers exhibit aneuploidy, but its functional significance in tumor development is controversial. Here, we describe ReDACT (Restoring Disomy in Aneuploid cells using CRISPR Targeting), a set of chromosome engineering tools that allow us to eliminate specific aneuploidies from cancer genomes. Using ReDACT, we created a panel of isogenic cells that have or lack common aneuploidies, and we demonstrate that trisomy of chromosome 1q is required for malignant growth in cancers harboring this alteration. Mechanistically, gaining chromosome 1q increases the expression of MDM4 and suppresses TP53 signaling, and we show that TP53 mutations are mutually-exclusive with 1q aneuploidy in human cancers...
January 10, 2023: bioRxiv
#15
JOURNAL ARTICLE
Norman Salomao, Nabih Maslah, Anouk Giulianelli, Louis Drevon, Lorea Aguinaga, Xiaolian Gu, Bruno Cassinat, Stephane Giraudier, Pierre Fenaux, Robin Fahraeus
The human homologues of murine double minute 2 (MDM2) and 4 (MDM4) negatively regulate p53 tumour suppressor activity and are reported to be frequently overexpressed in human malignancies, prompting clinical trials with drugs that prevent interactions between MDM2/MDM4 and p53. Bone marrow samples from 111 patients with acute myeloblastic leukaemia, myelodysplastic syndrome or chronic myelomonocytic leukaemia were examined for protein (fluorescence-activated cell sorting) and messenger RNA (mRNA) expression (quantitative polymerase chain reaction) of MDM2, MDM4 and tumour protein p53 (TP53)...
December 22, 2022: British Journal of Haematology
#16
JOURNAL ARTICLE
Javier Octavio Mejía-Hernández, Dinesh Raghu, Franco Caramia, Nicholas Clemons, Kenji Fujihara, Thomas Riseborough, Amina Teunisse, Aart G Jochemsen, Lars Abrahmsén, Giovanni Blandino, Andrea Russo, Cristina Gamell, Stephen B Fox, Catherine Mitchell, Elena A Takano, David Byrne, Panimaya Jeffreena Miranda, Reem Saleh, Heather Thorne, Shahneen Sandhu, Scott G Williams, Simon P Keam, Ygal Haupt, Sue Haupt
Metastatic prostate cancer is a lethal disease in patients incapable of responding to therapeutic interventions. Invasive prostate cancer spread is caused by failure of the normal anti-cancer defense systems that are controlled by the tumour suppressor protein, p53. Upon mutation, p53 malfunctions. Therapeutic strategies to directly re-empower the growth-restrictive capacities of p53 in cancers have largely been unsuccessful, frequently because of a failure to discriminate responses in diseased and healthy tissues...
August 16, 2022: Cancers
#17
JOURNAL ARTICLE
Frank P B Dubois, Ofer Shapira, Noah F Greenwald, Travis Zack, Jeremiah Wala, Jessica W Tsai, Alexander Crane, Audrey Baguette, Djihad Hadjadj, Ashot S Harutyunyan, Kiran H Kumar, Mirjam Blattner-Johnson, Jayne Vogelzang, Cecilia Sousa, Kyung Shin Kang, Claire Sinai, Dayle K Wang, Prasidda Khadka, Kathleen Lewis, Lan Nguyen, Hayley Malkin, Patricia Ho, Ryan O'Rourke, Shu Zhang, Rose Gold, Davy Deng, Jonathan Serrano, Matija Snuderl, Chris Jones, Karen D Wright, Susan N Chi, Jacques Grill, Claudia L Kleinman, Liliana C Goumnerova, Nada Jabado, David T W Jones, Mark W Kieran, Keith L Ligon, Rameen Beroukhim, Pratiti Bandopadhayay
We analyzed the contributions of structural variants (SVs) to gliomagenesis across 179 pediatric high-grade gliomas (pHGGs). The most recurrent SVs targeted MYC isoforms and receptor tyrosine kinases (RTKs), including an SV amplifying a MYC enhancer in 12% of diffuse midline gliomas (DMG), indicating an underappreciated role for MYC in pHGG. SV signature analysis revealed that tumors with simple signatures were TP53 wild type (TP53WT ) but showed alterations in TP53 pathway members PPM1D and MDM4. Complex signatures were associated with direct aberrations in TP53, CDKN2A and RB1 early in tumor evolution and with later-occurring extrachromosomal amplicons...
August 2022: Nature Cancer
#18
JOURNAL ARTICLE
Wei Huang, Cheng Zhang, Shida Xiong, Xiaocheng Zhou, Gongxian Wang, Ju Guo
BACKGROUND: Emerging evidence has shown that miR-1307-5p is involved in tumorigenesis of various types of cancer. This study aims to assess the role and mechanism of miR-1307-5p in bladder cancer. METHODS: Bioinformatics analyses were carried out with clinical datasets in the public domains. To investigate the cellular functions of miR-1307-5p, assays of cell proliferation, cell cycle and cell apoptosis were conducted in bladder cancer cell lines and xenografts...
July 1, 2022: Discover. Oncology
#19
JOURNAL ARTICLE
Taylor E Arnoff, Wafik S El-Deiry
Metastatic melanoma has a five-year survival of ~10%, with a paucity of biomarkers predicting metastasis to specific anatomic sites or targeted therapies for metastases. We analyzed 1015 primary and 358 metastatic melanomas and found metastatic disease is enriched for MDM2 and MDM4 amplifications compared to primary disease, and amplifications are associated with lower overall survival. MDM2/4 amplifications are associated with a higher rate of metastasis to the brain and liver. Two negative regulators of p53, USP7 and PPM1D , are also altered in metastatic melanoma compared to primary disease...
2022: American Journal of Cancer Research
#20
JOURNAL ARTICLE
Gregory R Bean, Saleh Najjar, Sandra J Shin, Elizabeth M Hosfield, Jennifer L Caswell-Jin, Anatoly Urisman, Kirk D Jones, Yunn-Yi Chen, Gregor Krings
Neuroendocrine carcinomas (NEC) of the breast are exceedingly rare tumors, which are classified in the WHO system as small cell (SCNEC) and large cell (LCNEC) carcinoma based on indistinguishable features from their lung counterparts. In contrast to lung and enteropancreatic NEC, the genomics of breast NEC have not been well-characterized. In this study, we examined the clinicopathologic, immunohistochemical, and genetic features of 13 breast NEC (7 SCNEC, 4 LCNEC, 2 NEC with ambiguous small versus large cell morphology [ANEC])...
May 19, 2022: Modern Pathology
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