27 results match your criteria atm kmt2a

  • Page 1 of 1

The CADM1 tumor suppressor gene is a major candidate gene in MDS with deletion of the long arm of chromosome 11.

Blood Adv 2021 Oct 12. Epub 2021 Oct 12.

Belgian Cancer Registry, Brussels, Belgium.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem-cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic and molecular levels. Read More

View Article and Full-Text PDF
October 2021

Genomic landscape of B-other acute lymphoblastic leukemia in an adult retrospective cohort with a focus on -like subtype.

Acta Oncol 2021 Jun 22;60(6):760-770. Epub 2021 Mar 22.

Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czechia.

Introduction: -like acute lymphoblastic leukemia (ALL) is a high-risk disease with a complex genomic background. Though extensively studied, data on the frequency and mutual associations of present mutations are still incomplete in adult patients. This retrospective study aims to map the genomic landscape of B-other ALL in a cohort of adult patients with a focus on the -like ALL subtype. Read More

View Article and Full-Text PDF

The mutational repertoire of uterine sarcomas and carcinosarcomas in a Brazilian cohort: A preliminary study.

Clinics (Sao Paulo) 2021 20;76:e2324. Epub 2021 Jan 20.

Laboratorio de Ginecologia Estrutural e Molecular, Disciplina de Ginecologia, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR.

Objectives: The present study aimed to contribute to the catalog of genetic mutations involved in the carcinogenic processes of uterine sarcomas (USs) and carcinosarcomas (UCSs), which may assist in the accurate diagnosis of, and selection of treatment regimens for, these conditions.

Methods: We performed gene-targeted next-generation sequencing (NGS) of 409 cancer-related genes in 15 US (7 uterine leiomyosarcoma [ULMS], 7 endometrial stromal sarcoma [ESS], 1 adenosarcoma [ADS]), 5 UCS, and 3 uterine leiomyoma (ULM) samples. Quality, frequency, and functional filters were applied to select putative somatic variants. Read More

View Article and Full-Text PDF

The role of autophagy in targeted therapy for acute myeloid leukemia.

Autophagy 2021 Oct 22;17(10):2665-2679. Epub 2020 Sep 22.

Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

Although molecular targeted therapies have recently displayed therapeutic effects in acute myeloid leukemia (AML), limited response and acquired resistance remain common problems. Numerous studies have associated autophagy, an essential degradation process involved in the cellular response to stress, with the development and therapeutic response of cancers including AML. Thus, we review studies on the role of autophagy in AML development and summarize the linkage between autophagy and several recurrent genetic abnormalities in AML, highlighting the potential of capitalizing on autophagy modulation in targeted therapy for AML. Read More

View Article and Full-Text PDF
October 2021

Genetic mutations and features of mantle cell lymphoma: a systematic review and meta-analysis.

Blood Adv 2020 07;4(13):2927-2938

Department of Lymphoma and Myeloma and.

Mantle cell lymphoma (MCL) is an incurable rare subtype of non-Hodgkin lymphoma and is subject to relapse and therapeutic resistance. Molecular aberrations in MCL affect pathogenesis, prognosis, and therapeutic response. In this systematic review, we searched 3 databases and selected 32 articles that described mutations in MCL patients. Read More

View Article and Full-Text PDF

Specific Genomic Alterations in High-Grade Pulmonary Neuroendocrine Tumours with Carcinoid Morphology.

Neuroendocrinology 2021 3;111(1-2):158-169. Epub 2020 Feb 3.

Department of Pathology, ENETS Centre of Excellence, Beaujon-Bichat Hospitals, AP-HP, Paris, France.

Introduction: High-grade lung neuroendocrine tumours with carcinoid morphology have been recently reported; they may represent the thoracic counterparts of grade 3 digestive neuroendocrine tumours. We aimed to study their genetic landscape including analysis of tumoral heterogeneity.

Methods: Eleven patients with high-grade (>20% Ki-67 and/or >10 mitoses) lung neuroendocrine tumours with a carcinoid morphology were included. Read More

View Article and Full-Text PDF
October 2021

Co-inhibition of HDAC and MLL-menin interaction targets MLL-rearranged acute myeloid leukemia cells via disruption of DNA damage checkpoint and DNA repair.

Clin Epigenetics 2019 10 7;11(1):137. Epub 2019 Oct 7.

Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, China.

While the aberrant translocation of the mixed-lineage leukemia (MLL) gene drives pathogenesis of acute myeloid leukemia (AML), it represents an independent predictor for poor prognosis of adult AML patients. Thus, small molecule inhibitors targeting menin-MLL fusion protein interaction have been emerging for the treatment of MLL-rearranged AML. As both inhibitors of histone deacetylase (HDAC) and menin-MLL interaction target the transcription-regulatory machinery involving epigenetic regulation of chromatin remodeling that governs the expression of genes involved in tumorigenesis, we hypothesized that these two classes of agents might interact to kill MLL-rearranged (MLL-r) AML cells. Read More

View Article and Full-Text PDF
October 2019

Genotoxic stress-triggered β-catenin/JDP2/PRMT5 complex facilitates reestablishing glutathione homeostasis.

Nat Commun 2019 08 21;10(1):3761. Epub 2019 Aug 21.

Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

The mechanisms underlying how cells subjected to genotoxic stress reestablish reduction-oxidation (redox) homeostasis to scavenge genotoxic stress-induced reactive oxygen species (ROS), which maintains the physiological function of cellular processes and cell survival, remain unclear. Herein, we report that, via a TCF-independent mechanism, genotoxic stress induces the enrichment of β-catenin in chromatin, where it forms a complex with ATM phosphorylated-JDP2 and PRMT5. This elicits histone H3R2me1/H3R2me2s-induced transcriptional activation by the recruitment of the WDR5/MLL methyltransferase complexes and concomitant H3K4 methylation at the promoters of multiple genes in GSH-metabolic cascade. Read More

View Article and Full-Text PDF

Non-leukemic pediatric mixed phenotype acute leukemia/lymphoma: Genomic characterization and clinical outcome in a prospective trial for pediatric lymphoblastic lymphoma.

Genes Chromosomes Cancer 2019 06 21;58(6):365-372. Epub 2019 Jan 21.

Department of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrechts University, Kiel, Germany.

Rare cases of hematological precursor neoplasms fulfill the diagnostic criteria of mixed phenotype acute leukemia (MPAL), characterized by expression patterns of at least two hematopoietic lineages, for which a highly aggressive behavior was reported. We present a series of 11 pediatric non-leukemic MPAL identified among 146 precursor lymphoblastic lymphomas included in the prospective trial Euro-LBL 02. Paraffin-embedded biopsies of 10 cases were suitable for molecular analyses using OncoScan assay (n = 7), fluorescence in situ hybridization (FISH; n = 7) or both (n = 5). Read More

View Article and Full-Text PDF

Somatic mutational profiles of stage II and III gastric cancer according to tumor microenvironment immune type.

Genes Chromosomes Cancer 2019 01 16;58(1):12-22. Epub 2018 Oct 16.

Department of Pathology, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea.

We aimed to determine somatic mutational profiles of stage II/III gastric cancers (GCs) according to their tumor microenvironment immune types (TMITs), which classify cancer based on co-assessment of PD-L1 expression and CD8 tumor infiltrating lymphocytes. Eighty patients with stage II/III GC were classified as follows: TMIT I (PD-L1 /CD8 ), TMIT II (PD-L1 /CD8 ), TMIT III (PD-L1 /CD8 ), and TMIT IV (PD-L1 /CD8 ). Deep targeted sequencing using a panel of 170 cancer-related genes was performed on an Illumina HiSeq-2500 system. Read More

View Article and Full-Text PDF
January 2019

An uncommon t(9;11)(p24;q22) with monoallelic loss of and genes in a child with myelodysplastic syndrome/acute myeloid leukemia who evolved from Fanconi anemia.

Mol Cytogenet 2018 11;11:40. Epub 2018 Jul 11.

1Bone Marrow Transplatation Center (CEMO), National Cancer Institute (INCA), Rio de Janeiro, Brazil.

Background: Myelodysplastic syndrome (MDS) is rare in the pediatric age group and it may be associated with inheritable bone marrow failure (BMF) such as Fanconi anemia (FA). FA is a rare multi-system genetic disorder, characterized by congenital malformations and progressive BMF. Patients with FA usually present chromosomal aberrations when evolving to MDS or acute myeloid leukemia (AML). Read More

View Article and Full-Text PDF

Quercetin alters the DNA damage response in human hematopoietic stem and progenitor cells via TopoII- and PI3K-dependent mechanisms synergizing in leukemogenic rearrangements.

Int J Cancer 2017 02 22;140(4):864-876. Epub 2016 Nov 22.

Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Quercetin (Que) is an abundant flavonoid in the human diet and high-concentration food supplement with reported pro- and anti-carcinogenic activities. Topoisomerase II (TopoII) inhibition and subsequent DNA damage induction by Que was implicated in the mixed lineage leukemia gene (MLL) rearrangements that can induce infant and adult leukemias. This notion raised concerns regarding possible genotoxicities of Que in hematopoietic stem and progenitor cells (HSPCs). Read More

View Article and Full-Text PDF
February 2017

Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML.

Sci Signal 2016 09 13;9(445):ra91. Epub 2016 Sep 13.

Genomic Instability Group; Spanish National Cancer Research Center (CNIO); Madrid 28029, Spain.

Among the various subtypes of acute myeloid leukemia (AML), those with chromosomal rearrangements of the MLL oncogene (AML-MLL) have a poor prognosis. AML-MLL tumor cells are resistant to current genotoxic therapies because of an attenuated response by p53, a protein that induces cell cycle arrest and apoptosis in response to DNA damage. In addition to chemicals that damage DNA, efforts have focused on targeting DNA repair enzymes as a general chemotherapeutic approach to cancer treatment. Read More

View Article and Full-Text PDF
September 2016

Collecting duct carcinoma of the kidney is associated with CDKN2A deletion and SLC family gene up-regulation.

Oncotarget 2016 May;7(21):29901-15

Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.

The genetic landscape and molecular features of collecting duct carcinoma (CDC) of the kidney remain largely unknown. Herein, we performed whole exome sequencing (WES) and transcriptome sequencing (RNASeq) on 7 CDC samples (CDC1 -7). Among the 7 samples, 4 samples with matched non-tumor tissue were used for copy number analysis by SNP array data. Read More

View Article and Full-Text PDF

MLL1 is essential for the senescence-associated secretory phenotype.

Genes Dev 2016 Feb;30(3):321-36

Epigenetics Program, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;

Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Read More

View Article and Full-Text PDF
February 2016

Dysregulation of the DNA Damage Response and KMT2A Rearrangement in Fetal Liver Hematopoietic Cells.

PLoS One 2015 11;10(12):e0144540. Epub 2015 Dec 11.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.

Etoposide, a topoisomerase 2 (TOP2) inhibitor, is associated with the development of KMT2A (MLL)-rearranged infant leukemia. An epidemiological study suggested that in utero exposure to TOP2 inhibitors may be involved in generation of KMT2A (MLL) rearrangement. The present study examined the mechanism underlying the development of KMT2A (MLL)-rearranged infant leukemia in response to in utero exposure to etoposide in a mouse model. Read More

View Article and Full-Text PDF

Distinctive genotypes in infants with T-cell acute lymphoblastic leukaemia.

Br J Haematol 2015 Nov 24;171(4):574-84. Epub 2015 Jul 24.

Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.

Infant T-cell acute lymphoblastic leukaemia (iT-ALL) is a very rare and poorly defined entity with a poor prognosis. We assembled a unique series of 13 infants with T-ALL, which allowed us to identify genotypic abnormalities and to investigate prenatal origins. Matched samples (diagnosis/remission) were analysed by single nucleotide polymorphism-array to identify genomic losses and gains. Read More

View Article and Full-Text PDF
November 2015

Endonuclease G initiates DNA rearrangements at the MLL breakpoint cluster upon replication stress.

Oncogene 2015 Jun 18;34(26):3391-401. Epub 2014 Aug 18.

Gynecological Oncology, Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.

MLL (myeloid/lymphoid or mixed-lineage leukemia) rearrangements are frequent in therapy-related and childhood acute leukemia, and are associated with poor prognosis. The majority of the rearrangements fall within a 7.3-kb MLL breakpoint cluster region (MLLbcr), particularly in a 0. Read More

View Article and Full-Text PDF

MEN1 is a melanoma tumor suppressor that preserves genomic integrity by stimulating transcription of genes that promote homologous recombination-directed DNA repair.

Mol Cell Biol 2013 Jul 6;33(13):2635-47. Epub 2013 May 6.

Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Multiple endocrine neoplasia type 1 is a familial cancer syndrome resulting from loss-of-function mutations in the MEN1 gene. We previously identified the tumor suppressor MEN1 as a gene required for oncogene-induced senescence in melanocytes, raising the possibility that MEN1 is a melanoma tumor suppressor. Here we show that MEN1 expression is lost in a high percentage of human melanomas and melanoma cell lines. Read More

View Article and Full-Text PDF

Ataxia telangiectasia mutated-dependent regulation of topoisomerase II alpha expression and sensitivity to topoisomerase II inhibitor.

Cancer Sci 2013 Feb 13;104(2):178-84. Epub 2013 Jan 13.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.

Topoisomerase II alpha (TOP2A) has a crucial role in proper chromosome condensation and segregation. Here we report the interaction of TOP2A with ataxia telangiectasia mutated (ATM) and its phosphorylation in an ATM-dependent manner after DNA damage. In vitro kinase assay and site-directed mutagenesis studies revealed that serine 1512 is the target of phosphorylation through ATM. Read More

View Article and Full-Text PDF
February 2013

DNA damage response and inflammatory signaling limit the MLL-ENL-induced leukemogenesis in vivo.

Cancer Cell 2012 Apr;21(4):517-31

Department of Biology, Palacky University, Olomouc, Czech Republic.

Activation of the MLL-ENL-ERtm oncogene initiates aberrant proliferation of myeloid progenitors. Here, we show induction of a fail-safe mechanism mediated by the DNA damage response (DDR) machinery that results in activation of the ATR/ATM-Chk1/Chk2-p53/p21(CIP1) checkpoint and cellular senescence at early stages of cellular transformation caused by a regulatable MLL-ENL-ERtm in mice. Furthermore, we identified the transcription program underlying this intrinsic anticancer barrier, and DDR-induced inflammatory regulators that fine-tune the signaling toward senescence, thereby modulating the fate of MLL-ENL-immortalized cells in a tissue-environment-dependent manner. Read More

View Article and Full-Text PDF

Prenatal exposure to flavonoids: implication for cancer risk.

Toxicol Sci 2011 Mar 21;120(1):59-67. Epub 2010 Dec 21.

Department of Health Risk Analysis and Toxicology, Nutrition and Toxicology Research, Institute Maastricht, Maastricht University, 6200 MD Maastricht, The Netherlands.

Flavonoids are potent antioxidants, freely available as high-dose dietary supplements. However, they can induce DNA double-strand breaks (DSB) and rearrangements in the mixed-lineage leukemia (MLL) gene, which are frequently observed in childhood leukemia. We hypothesize that a deficient DSB repair, as a result of an Atm mutation, may reinforce the clastogenic effect of dietary flavonoids and increase the frequency of Mll rearrangements. Read More

View Article and Full-Text PDF

ATM modulates the loading of recombination proteins onto a chromosomal translocation breakpoint hotspot.

PLoS One 2010 Oct 27;5(10):e13554. Epub 2010 Oct 27.

Department of Cellular Biology, RIRBM, Hiroshima University, Hiroshima, Japan.

Chromosome translocations induced by DNA damaging agents, such as ionizing radiation and certain chemotherapies, alter genetic information resulting in malignant transformation. Abrogation or loss of the ataxia-telangiectasia mutated (ATM) protein, a DNA damage signaling regulator, increases the incidence of chromosome translocations. However, how ATM protects cells from chromosome translocations is still unclear. Read More

View Article and Full-Text PDF
October 2010

The value of fluorescence in situ hybridization for the detection of 11q in multiple myeloma.

Haematologica 2004 Oct;89(10):1213-8

Departamento de Hematología, Hospital Universitario & Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC, Spain.

Background And Objectives: A large number of chromosomal abnormalities have been detected in multiple myeloma (MM). The most frequent are chromosome 13q deletions and translocations affecting the immunoglobulin heavy chain gene (IGH). Recent studies using comparative genomic hybridization (CGH) have shown that gains of 11q represent one of the most frequent genomic changes in MM. Read More

View Article and Full-Text PDF
October 2004

Missense mutation and defective function of ATM in a childhood acute leukemia patient with MLL gene rearrangement.

Blood 2003 May 2;101(9):3622-7. Epub 2003 Jan 2.

Department of Pediatrics and Developmental Biology, Postgraduate Medical School, Tokyo Medical and Dental University, Tokyo, Japan.

The possible involvement of germline mutation of the ataxia telangiectasia mutated (ATM) gene in childhood acute leukemia with mixed lineage leukemia (MLL) gene rearrangement (MLL(+)) was investigated. Of the 7 patients studied, 1 showed a germline missense ATM mutation (8921C>T; Pro2974Leu), located in the phosphatidylinositol-3 (PI-3) kinase domain. In reconstitution assays, the ATM mutant 8921T could only partially rescue the radiosensitive phenotype of AT fibroblasts, and in an in vitro kinase assay, it showed a defective phosphorylation of p53-Ser15. Read More

View Article and Full-Text PDF

GPHN, a novel partner gene fused to MLL in a leukemia with t(11;14)(q23;q24).

Genes Chromosomes Cancer 2001 Nov;32(3):212-21

Leukaemia Research Fund Centre, Institute of Cancer Research, London, United Kingdom.

We report a novel MLL-associated chromosome translocation t(11;14)(q23;q24) in a child who showed signs of acute undifferentiated leukemia 3 years after intensive chemotherapy that included the topoisomerase-II inhibitor VP 16. Screening of a cDNA library of the patient's leukemic cells showed a novel fusion transcript between MLL and the Gephyrin (GPHN) gene on 14q24. The resulting MLL-GPHN fusion gene encodes MLL AT hook motifs and a DNA methyltransferase homology domain fused to the C-terminal half of Gephyrin, including a presumed tubulin binding site and a domain homologous to the Escherichia coli molybdenum cofactor biosynthesis protein MoeA. Read More

View Article and Full-Text PDF
November 2001
  • Page 1 of 1