Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared with SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.

• MeSH
• dítě MeSH
• fúzní onkogenní proteiny genetika   MeSH
• genová přestavba * MeSH
• gliom klasifikace   genetika   patologie   MeSH
• kohortové studie MeSH
• kojenec MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy genetika   MeSH
• mladiství MeSH
• mutace * MeSH
• nádorové biomarkery genetika   MeSH
• nádory mozku klasifikace   genetika   patologie   MeSH
• neurofibromin 1 genetika   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• protoonkogenní proteiny B-raf genetika   MeSH
• ras proteiny genetika   MeSH
• regulace genové exprese u nádorů * MeSH
• stanovení celkové genové exprese MeSH
• variabilita počtu kopií segmentů DNA * MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Chimeric antigen receptor anti-CD19 (CAR19)-T cell immunotherapy-induced clinical remissions in CD19+ B cell lymphomas are often short lived. We tested whether CAR19-engineering of the CD1d-restricted invariant natural killer T (iNKT) cells would result in enhanced anti-lymphoma activity. CAR19-iNKT cells co-operatively activated by CD1d- and CAR19-CD19-dependent interactions are more effective than CAR19-T cells against CD1d-expressing lymphomas in vitro and in vivo. The swifter in vivo anti-lymphoma activity of CAR19-iNKT cells and their enhanced ability to eradicate brain lymphomas underpinned an improved tumor-free and overall survival. CD1D transcriptional de-repression by all-trans retinoic acid results in further enhanced cytotoxicity of CAR19-iNKT cells against CD19+ chronic lymphocytic leukemia cells. Thus, iNKT cells are a highly efficient platform for CAR-based immunotherapy of lymphomas and possibly other CD1d-expressing cancers.

• MeSH
• antigeny CD19 genetika   imunologie   MeSH
• antigeny CD1d genetika   imunologie   MeSH
• buněčná a tkáňová terapie * MeSH
• chronická lymfatická leukemie genetika   imunologie   MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• lymfom farmakoterapie   imunologie   MeSH
• myši MeSH
• NKT buňky cytologie   imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

• MeSH
• genomika MeSH
• individualizovaná medicína * MeSH
• kohortové studie MeSH
• lidé MeSH
• meduloblastom klasifikace   genetika   terapie   MeSH
• metylace DNA MeSH
• shluková analýza MeSH
• stanovení celkové genové exprese MeSH
• variabilita počtu kopií segmentů DNA MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed.

• MeSH
• Atg5 genetika   MeSH
• autofagie MeSH
• citráty aplikace a dávkování   farmakologie   MeSH
• experimentální nádory dietoterapie   farmakoterapie   imunologie   MeSH
• kalorická restrikce metody   MeSH
• lidé MeSH
• methotrexát aplikace a dávkování   farmakologie   MeSH
• monitorování imunologické MeSH
• mutace MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• protoonkogenní proteiny p21(ras) genetika   MeSH
• regulační T-lymfocyty účinky léků   MeSH
• spermidin aplikace a dávkování   farmakologie   MeSH
• transplantace nádorů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed 192 ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets.

• MeSH
• chromozomální proteiny, nehistonové genetika   MeSH
• DNA vazebné proteiny genetika   MeSH
• epigeneze genetická genetika   MeSH
• lidé MeSH
• mutace genetika   MeSH
• nádory mozku genetika   MeSH
• rhabdoidní nádor genetika   MeSH
• teratom genetika   MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The regulation and stem cell origin of normal and neoplastic gastric glands are uncertain. Here, we show that Mist1 expression marks quiescent stem cells in the gastric corpus isthmus. Mist1(+) stem cells serve as a cell-of-origin for intestinal-type cancer with the combination of Kras and Apc mutation and for diffuse-type cancer with the loss of E-cadherin. Diffuse-type cancer development is dependent on inflammation mediated by Cxcl12(+) endothelial cells and Cxcr4(+) gastric innate lymphoid cells (ILCs). These cells form the perivascular gastric stem cell niche, and Wnt5a produced from ILCs activates RhoA to inhibit anoikis in the E-cadherin-depleted cells. Targeting Cxcr4, ILCs, or Wnt5a inhibits diffuse-type gastric carcinogenesis, providing targets within the neoplastic gastric stem cell niche.

• MeSH
• anoikis MeSH
• antitumorózní látky farmakologie   MeSH
• buněčný rodokmen MeSH
• časové faktory MeSH
• chemokin CXCL12 metabolismus   MeSH
• endoteliální buňky metabolismus   patologie   MeSH
• epitelové buňky účinky léků   metabolismus   patologie   MeSH
• kadheriny metabolismus   MeSH
• lidé MeSH
• lymfocyty metabolismus   patologie   MeSH
• mezibuněčná komunikace MeSH
• myši transgenní MeSH
• myši MeSH
• nádorová transformace buněk genetika   metabolismus   patologie   MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky účinky léků   metabolismus   patologie   MeSH
• nádorové mikroprostředí * MeSH
• nádory žaludku farmakoterapie   genetika   metabolismus   patologie   MeSH
• nika kmenových buněk * MeSH
• proteiny Wnt metabolismus   MeSH
• receptory CXCR4 metabolismus   MeSH
• rho proteiny vázající GTP metabolismus   MeSH
• signální dráha Wnt MeSH
• signální transdukce MeSH
• stárnutí buněk MeSH
• transkripční faktory bHLH genetika   metabolismus   MeSH
• transplantace kostní dřeně MeSH
• žaludeční sliznice účinky léků   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based on its lack of reproducibility in predicting patients' outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.

• MeSH
• adaptorové proteiny signální transdukční genetika   MeSH
• dítě MeSH
• dospělí MeSH
• ependymom klasifikace   genetika   patologie   MeSH
• fosfoproteiny genetika   MeSH
• fúze genů MeSH
• genetická transkripce MeSH
• genová dávka MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• metylace DNA MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádory centrálního nervového systému klasifikace   genetika   patologie   MeSH
• předškolní dítě MeSH
• senioři MeSH
• stanovení celkové genové exprese MeSH
• věkové faktory * MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

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. Our results indicate that DDR is a rate-limiting event for acquisition of stem cell-like properties in MLL-ENL-ERtm-mediated transformation, as experimental inhibition of the barrier accelerated the transition to immature cell states and acute leukemia development.

• MeSH
• DNA vazebné proteiny genetika   MeSH
• fúzní onkogenní proteiny genetika   MeSH
• genový knockin MeSH
• kofein farmakologie   MeSH
• kontrolní body buněčného cyklu genetika   MeSH
• leukemie genetika   MeSH
• lidé MeSH
• myši MeSH
• nádorová transformace buněk MeSH
• nádorové kmenové buňky patologie   MeSH
• poškození DNA MeSH
• proliferace buněk MeSH
• protoonkogenní protein MLL genetika   MeSH
• regulace genové exprese u nádorů MeSH
• signální transdukce MeSH
• transkripční faktory genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cells exposed to genotoxic insults such as ionizing radiation activate a signaling cascade to repair the damaged DNA. Two recent articles published in Nature show that such genome maintenance requires modifications of tumor suppressor proteins BRCA1 and 53BP1 by the small ubiquitin-like modifier SUMO. Copyright (c) 2010 Elsevier Inc. All rights reserved.

• MeSH
• intracelulární signální peptidy a proteiny metabolismus   MeSH
• lidé MeSH
• nádory * genetika   metabolismus   MeSH
• oprava DNA * fyziologie   MeSH
• poškození DNA * fyziologie   MeSH
• protein BRCA1 metabolismus   MeSH
• protein SUMO-1 * metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH

Through its roles in cell cycle control and DNA damage response, microcephalin (also known as BRIT1 or MCPH1) has been implicated in fundamental biological processes, including regulation of brain size and maintenance of genomic integrity. Two new reports in Nature Cell Biology and this issue of Cancer Cell provide further insights into the functions of microcephalin in DNA damage checkpoints and timing of mitosis. Depletion or disease-associated mutations of microcephalin resulted in centrosomal abnormalities and chromosomal instability. These findings and aberrantly reduced expression in human carcinomas identify microcephalin as a candidate novel tumor suppressor.

• MeSH
• buněčný cyklus * fyziologie   MeSH
• chromozomální aberace MeSH
• lidé MeSH
• mitóza fyziologie   MeSH
• mozek * abnormality   MeSH
• mutace MeSH
• nádorové supresorové proteiny fyziologie   genetika   MeSH
• nádory genetika   metabolismus   patologie   MeSH
• nestabilita genomu * fyziologie   MeSH
• poškození DNA fyziologie   MeSH
• proteiny nervové tkáně fyziologie   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH