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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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LIN28B is overexpressed in specific subtypes of pediatric leukemia and regulates lncRNA H19 [K562]

ABSTRACT: The stem cell gene LIN28B was recently shown to be overexpressed in a foetal-like subgroup of juvenile myelomonocytic leukaemia. Given the involvement of LIN28B in a variety of solid paediatric cancers, we conducted a meta-analysis of LIN28B levels using publicly available gene expression data of 1361 paediatric leukaemia samples. Interestingly, this analysis revealed LIN28B overexpression in 102 childhood leukaemia patients (7.5%), suggesting oncogenic activity for LIN28B in the context of paediatric haematological diseases. As the mode of action of LIN28B during normal and malignant haematopoiesis remains largely unexplored, we subsequently analysed the transcriptional consequences of LIN28B modulation on normal and malignant haematopoietic cells and identified the long non-coding RNA (lncRNA) H19 as the first LIN28B-regulated lncRNA. K562 cells were retrovirally transduced with shRNA GN36578 against LIN28B and a shRNA-miR non-targeting control TRH1103 (both Transomic), selected with puromycin and hybridized on Agilent microarray.

ORGANISM(S): Homo sapiens

SUBMITTER: Hetty Helsmoortel

PROVIDER: E-GEOD-79980 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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LIN28B is overexpressed in specific subtypes of pediatric leukemia and regulates lncRNA H19 [Oci-AML3]

Project description:The stem cell gene LIN28B was recently shown to be overexpressed in a foetal-like subgroup of juvenile myelomonocytic leukaemia. Given the involvement of LIN28B in a variety of solid paediatric cancers, we conducted a meta-analysis of LIN28B levels using publicly available gene expression data of 1361 paediatric leukaemia samples. Interestingly, this analysis revealed LIN28B overexpression in 102 childhood leukaemia patients (7.5%), suggesting oncogenic activity for LIN28B in the context of paediatric haematological diseases. As the mode of action of LIN28B during normal and malignant haematopoiesis remains largely unexplored, we subsequently analysed the transcriptional consequences of LIN28B modulation on normal and malignant haematopoietic cells and identified the long non-coding RNA (lncRNA) H19 as the first LIN28B-regulated lncRNA. Oci-AML3 cells were retrovirally transduced with MSCV-PIG-LIN28B and MSCV-PIG-empty vectors (gifts from Johua Mendel lab), selected with puromycin and hybridized on Agilent microarray.

2016-04-07 | E-GEOD-79979 | biostudies-arrayexpress

LIN28B is overexpressed in specific subtypes of pediatric leukemia and regulates lncRNA H19 [K562]

2016-04-07 | GSE79980 | GEO

LIN28B is overexpressed in specific subtypes of pediatric leukemia and regulates lncRNA H19 [Oci-AML3]

2016-04-07 | GSE79979 | GEO

LIN28B is overexpressed in specific subtypes of pediatric leukemia and regulates lncRNA H19

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-04-07 | E-GEOD-79981 | biostudies-arrayexpress

Identification of novel long non-coding RNAs as biomarker for patients with renal cell carcinoma

Project description:Long non-coding RNAs (lncRNA) play an important role in carcinogenesis, but knowledge of lncRNA expression in renal cell carcinoma is rudimental. We screened 32,183 lncRNA transcripts in malignant and adjacent normal renal tissue and determined dysregulation of approximately 4% of the lncRNA transcripts in clear cell renal cell carcinoma tissue. The distinct changes of lncRNA expression may be used to develop a non-invasive biomarker, because lncRNAs are detectable in bodily fluids. Microarray experiments were performed to determine the expression of 32,183 lncRNA transcripts belonging to 17,512 lncRNAs in 15 corresponding normal and malignant renal tissues

2015-02-18 | E-GEOD-61763 | biostudies-arrayexpress

Ontogenic changes in hematopoietic hierarchy determine pediatric specificity and disease phenotype in fusion oncogene-driven myeloid leukemia - scRNAseq - 2

Project description:Paediatric cancers present specific genetic alterations, however the principles underlying their differences to adult cancers are yet unclear. Poor prognosis paediatric myeloid leukaemia fusion oncogenes represent clinically-relevant models to investigate age-specific tumorigenesis. Here, we established an inducible murine model to show that the ETO2-GLIS2 fusion induces both megakaryoblastic and myeloid leukaemia in a cellular and developmental stage-dependent manner, reproducing different age and phenotype associations observed in patients. The aggressive megakaryoblastic leukemia phenotype developed from haematopoietic stem cells and was associated with massive rewiring of master transcription factors activities (e.g. ERG, GATA and CEBPA). Switching off ETO2-GLIS2 expression in transformed cells restored some long-term haematopoietic stem cell potential. In contrast, targeting downstream progenitors was required for the myeloid phenotype. These data demonstrate that the promiscuity between HSC and megakaryocytic states and the ontogenic changes in the cellular architecture of the hematopoietic tissue controls paediatric and phenotype specificities in myeloid leukaemia.

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Blockade of oncogenic IkappaB kinase activity in ABC DLBCL by small molecule BET protein inhibitors

Project description:In the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), NF-kappaB activity is essential for viability of the malignant cells and is sustained by constitutive activity of IkappaB kinase (IKK) in the cytoplasm. Here, we report an unexpected role for the bromodomain and extraterminal domain (BET) proteins BRD2 and BRD4 in maintaining oncogenic IKK activity in ABC DLBCL. IKK activity was reduced by small molecules targeting BET proteins as well as by genetic knockdown of BRD2 and BRD4 expression, thereby inhibiting downstream NF-kappaB-driven transcriptional programs and killing ABC DLBCL cells. Using a high-throughput platform to screen for drug-drug synergy, we observed that the BET inhibitor JQ1 combined favorably with multiple drugs targeting B cell receptor signaling, one pathway that activates IKK in ABC DLBCL. The BTK kinase inhibitor ibrutinib, which is in clinical development for the treatment of ABC DLBCL, synergized strongly with BET inhibitors in killing ABC DLBCL cells in vitro and in a xenograft mouse model. These findings provide a mechanistic basis for the clinical development of BET protein inhibitors in ABC DLBCL, particularly in combination with other modulators of oncogenic IKK signaling. For JQ1 time course gene expression profiling, HBL1 and LP1 cells were treated with either DMSO or 100nM JQ1 for 1h, 3h, 8h, and 24h. For shRNA gene expression profiling, HBL1 cells were infected with either a Ctrl shRNA or with shRNA targeting BRD2 or BRD4. Following puromycin selection, shRNA expression was induced for 1 day and 2 days.

2014-08-01 | E-GEOD-58791 | biostudies-arrayexpress

Age-specific biological and molecular profiling distinguishes paediatric from adult acute myeloid leukaemias

Project description:Acute myeloid leukaemia (AML) affects children and adults of all ages. AML remains one of the major causes of death in children with cancer and for children with AML relapse is the most common cause of death. By modelling AML in vivo we demonstrate that AML is discriminated by the age of the cell of origin. Young cells give rise to myeloid, lymphoid or mixed phenotype acute leukaemia, whereas adult cells give rise exclusively to AML, with a shorter latency. Unlike adult, young AML cells do not remodel the bone marrow stroma. Transcriptional analysis distinguishes young AML by the upregulation of immune pathways. Analysis of human paediatric AML samples recapitulates a paediatric immune cell interaction gene signature, highlighting two genes, RGS10 and FAM26F as prognostically significant. This work advances our understanding of paediatric AML biology, and provides murine models that offer the potential for developing paediatric specific therapeutic strategies.

2018-11-04 | GSE122066 | GEO

Age-specific biological and molecular profiling distinguishes paediatric from adult acute myeloid leukaemias

Project description:Acute myeloid leukaemia (AML) affects children and adults of all ages. AML remains one of the major causes of death in children with cancer and for children with AML relapse is the most common cause of death. Here, by modelling AML in vivo we demonstrate that AML is discriminated by the age of the cell of origin. Young cells give rise to myeloid, lymphoid or mixed phenotype acute leukaemia, whereas adult cells give rise exclusively to AML, with a shorter latency. Unlike adult, young AML cells do not remodel the bone marrow stroma. Transcriptional analysis distinguishes young AML by the upregulation of immune pathways. Analysis of human paediatric AML samples recapitulates a paediatric immune cell interaction gene signature, highlighting two genes, RGS10 and FAM26F as prognostically significant. This work advances our understanding of paediatric AML biology, and provides murine models that offer the potential for developing paediatric specific therapeutic strategies.

2018-06-14 | GSE107662 | GEO

Gene expression profiling of 44 JMML patients and 7 healthy donors (discovery cohort)

Project description:Juvenile myelomonocytic leukemia (JMML) is a very rare and aggressive stem cell disease that mainly occurs in young children. RAS activation constitutes the core component of oncogenic signaling. In addition, the leukemic blasts of a quarter of JMML patients present with monosomy 7 (-7), whereas more than half of the patients show enhanced age-adjusted fetal hemoglobin (HbF) levels. Hematopoietic stem cell transplantation is the current standard of care. This results in an event-free survival of 50 - 60%, indicating that novel molecular driven therapeutic options are urgently needed. Using gene expression profiling in an extensive series of 82 patient samples, we aimed at understanding the molecular biology behind JMML and identified a previously unrecognized molecular subgroup characterized by high LIN28B expression. Interestingly, LIN28B overexpression was significantly correlated with higher HbF levels whereas patients with -7 seldom showed enhanced LIN28B expression. In line with LIN28Bâ??s role as mediator of fetal hematopoiesis, this explains the biology behind the observation that patients with -7 are rarely diagnosed with high age-adjusted HbF levels. In addition, this new fetal-like JMML subgroup presented with reduced levels of most members of the let-7 microRNA family and showed characteristic overexpression of genes involved in fetal hematopoiesis and stem cell self-renewal. Finally, high LIN28B expression was associated with poor clinical outcome in our JMML patient series, but not independent from other prognostic factors such as age and age-adjusted HbF levels. In conclusion, we identified LIN28B as a crucial molecular player at the heart of a novel fetal-like subgroup in JMML. Gene expression was measured on Agilent in 44 JMML patients and 7 healthy donors in the discovery cohort. A validation cohort of 38 patients and 9 healthy donors was measured on Affymetrix. All patient data can be found in Supplementary Table S1.

2015-12-23 | E-GEOD-71449 | biostudies-arrayexpress

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