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Exomes of human leukemic JMML (Juvenile MyeloMonocytic Leukemia) xenografts in NSG or NSG-S mice (samples enriched in hCD45)

ABSTRACT: Exomes of human leukemic JMML (Juvenile MyeloMonocytic Leukemia) xenografts in NSG or NSG-S mice (samples enriched in hCD45)

PROVIDER: PRJEB24819 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR2283610_1.fastq.gz	Fastqsanger.gz
	ERR2283610_2.fastq.gz	Fastqsanger.gz
	ERR2283620_1.fastq.gz	Fastqsanger.gz
	ERR2283620_2.fastq.gz	Fastqsanger.gz
	ERR2283611_1.fastq.gz	Fastqsanger.gz

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Exomes of human leukemic JMML (Juvenile MyeloMonocytic Leukemia) xenografts in NSG or NSG-S mice (samples enriched in hCD45)

Project description:The study includes 14 patients with confirmed JMML and known somatic mutations (from exome data of paired tumoral and germline DNA). Bone marrow or peripheral blood mononucleated cells were injected in immundeficient mice to recapitulate the leukemia. Whole exome sequencing was performed in xenograft samples to control the persistance of patients' known mutations and look for new mutations acquired in xenograft sample.

2018-03-15 | E-MTAB-6467 | biostudies-arrayexpress

Exomes of human leukemic JMML (Juvenile MyeloMonocytic Leukemia) cells and paired fibroblasts (germilne controls) when available

Project description:Exomes of human leukemic JMML (Juvenile MyeloMonocytic Leukemia) cells and paired fibroblasts (germilne controls) when available

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Proteomic analysis of an induced pluripotent stem cell model reveals strategies to treat Juvenile Myelomonocytic Leukaemia

Project description:Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of early childhood with a poor survival rate thus there is a requirement for improved treatment strategies. Induced pluripotent stem cells offer the ability to model disease and develop new treatment strategies. JMML is frequently associated with mutations in PTPN11. Children with Noonan syndrome, a development disorder, have an increased incidence of JMML associated with specific germline mutations in PTPN11. We undertook a proteomic assessment of myeloid cells derived from induced pluripotent stem cells obtained from Noonan syndrome patients with PTPN11 mutations, either associated or not associated with increased incidence of JMML. We report that the proteomic perturbations induced by the leukaemia-associated PTPN11 mutations are associated with TP53 and NF-ĸb signalling. We have previously shown that MYC is involved in the differential gene expression observed in Noonan syndrome patients associated with increased incidence of JMML. Thus, we employed drugs to target these pathways and demonstrate differentential effects on clonogenic hematopoietic cells derived from Noonan syndrome patients whom develop JMML and those who do not. Further, we demonstrated these small molecular inhibitors, JQ1 and CBL0137, preferentially extinguish primitive haematopoietic cells from sporadic JMML patients as opposed to cells from healthy individuals.

2019-10-30 | PXD014708 | Pride

Exomes of human leukemic JMML (Juvenile MyeloMonocytic Leukemia) cells and paired fibroblasts (germilne controls) when available

Project description:The study included 15 patients (7 males, 8 females) with JMML. Peripheral blood and/or bone marrow aspirates were collected on EDTA at diagnosis. Non-hematopoietic tissues (fibroblasts) was derived from skin biopsy for each patient. Exome sequencing was performed in several distinct series between 2012 and 2017, which explains the differences in capture kit versions and reference genome version.Targeted enrichment and massive parallel sequencing were performed on paired genomic DNA from leukocytes and fibroblasts. Exome capture was carried out using the SureSelect Human All Exon V4+UTRs or V5 or V5+UTRs or SureSelect Clinical Research (Agilent Technologies, Santa Clara, CA, USA) according to manufacturer’s instruction and protocols by IntegraGen (Evry, France). Paired-end 75 bases sequencing was performed on a HiSeq2000 or HiSeq4000 instrument (Illumina, San Diego, CA, USA). Image analysis and base calling were performed using the Real Time Analysis (RTA) pipeline v. 1.14 (Illumina) with default parameters. The alignment of paired-end reads to the reference human genome (UCSC GRCh37/hg19 or UCSC GRCh38), variant calling and generation of Quality variants scores were carried out using the CASAVA v.1.8 pipeline (Illumina).

2018-03-14 | E-MTAB-6461 | biostudies-arrayexpress

Transcriptome analysis of JMML patients compare to healthy prenatal and postnatal samples.

Project description:JMML (Juvenile myelomonocytic leukaemia) is a leukaemia that only develops in young children and is thought to have a prenatal initiation. To study the relationship between JMML and normal ontogeny we studied the transcriptome of HPC (hematopoietic progenitor cells) sorted from sporadic JMML patients, healthy prenatal samples and from healthy age matched donors. Bulk transcriptome of sorted HPC reveals that some JMML samples cluster with prenatal samples whereas other from a distinct cluster apart from any healthy samples.

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Kinome profiling of patient JMML samples pre- and post-trametinib treatment

Project description:Juvenile myelomonocytic leukemia (JMML) is an aggressive cancer of young children initiated by mutations in NRAS, KRAS and other genes encoding proteins that modulate Ras signal output. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment and patients with relapsed and refractory disease have dismal outcomes. This trial evaluated the safety and efficacy of trametinib in advanced JMML. Kinase enrichment proteomic analysis was performed using available patient samples pre- or post-treatment with trametinib (NCT03190915) to evaluate the effects on the functional kinome.

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Transcriptome and methylation analysis of JMML patients compare to healthy prenatal and postnatal samples.

Project description:JMML (Juvenile myelomonocytic leukaemia) is a leukaemia hat only develops in young children and is thought to have a prenatal initiation. To study the relationship between JMML and normal ontogeny we studied the transcriptome of HSPC (hematopoietic stem and progenitor cells) sorted from sporadic JMML patients, healthy prenatal samples and from healthy age matched donors. Bulk transcriptome of sorted HSPC reveals that some JMML samples cluster with prenatal samples whereas other from a distinct cluster apart from any healthy samples. Methylation profile on bulk mononucleated cell on theses JMML patients, 2 healthy postnatal and 2 healthy prenatal samples is also investigated. The results show a global hypermethylation in JMML samples compared to healthy samples and a specific JMML group with a hypermethylated profile compared to all JMML samples.

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Genomic and epigenomic characterization of juvenile myelomonocytic leukemia (JMML)

Project description:Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood. While some cases show spontaneous remission, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment option for the majority of patients, however, the 5-year event-free survival reaches only about 50%. Hyperactive RAS signaling is assumed to be the main driving event in JMML. It is caused by genetic alterations in CBL, KRAS, NF1, NRAS, or PTPN11 in about 90% of patients. So far, there is no clear understanding of how RAS pathway mutations relate to the heterogeneous disease biology and variable clinical outcome seen in JMML patients. As a consequence, established clinical and genetic markers fail to fully represent the observed disease heterogeneity. We hypothesized that DNA methylation profiling, either alone or in combination with genetic alterations, might provide a molecular basis for disease classification. Genome wide DNA methylation analysis using the HumanMethylation450 Bead Chip array was performed in a discovery cohort of 20 patients (19 JMML, 1 Noonan syndrome). The clinical relevance of our findings was assessed in an unselected sample set consisting of 147 consecutive patients with JMML (n=129) or Noonan syndrome (n=18) associated myeloproliferative disorder (n=18) registered in the EWOG-MDS 1998 & 2006 trials. Data integration was performed in a subset of patients with available exome sequencing (n=50) and expression profiling (n=15) data. This integrated approach identified three JMML subgroups characterized by distinct clinical and biological features. This analysis further suggested a molecular mechanism by which additional genetic events, presumably further activating the RAS-RAF-MEK-ERK pathway, mediate DNA hypermethylation via up-regulation of DNMTs in more aggressive JMML cases.

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Total paired-end RNA sequencing of bone marrow and peripheral blood MNCs from patients with Juvenile myelomonocytic leukemia and age-matched controls

Project description:Dysregulation of the non-coding RNA transcriptome has been demonstrated in Juvenile myelomonocytic leukemia (JMML), a rare and aggressive disorder of early childhood. Currently, JMML treatment relies on hematopoietic stem cell transplantation resulting in long-term overall survival of only 50-60%. Consequently, there is need to develop novel treatments. In this study we investigated the therapeutic potential of targeting overexpressed long non-coding RNAs (lncRNAs) in JMML. Total RNA sequencing from 19 previously untreated JMML patients and 3 pediatric normal bone marrow samples revealed 202 differentially expressed lncRNA genes (144 upregulated and 58 downregulated). Molecular knockdown (≥ 70% compared to mock control) after 24h of incubation was observed for 6 out of 10 overexpressed lncRNAs for which LNA GapmeRs were designed. For 3 lncRNAs (lnc-THADA-4-1, lnc-ACOT9-1 and NRIR) knockdown resulted in a significant effect on cell viability after 96h or 72h of incubation in cell lines or in primary JMML cells, respectively. Importantly, the extend of cellular damage correlated well with the expression of the lncRNA of interest. In conclusion, we provided proof-of-concept that knockdown of overexpressed lncRNAs such as lnc-THADA-4-1, lnc-ACOT9-1 and NRIR is a feasible therapeutic strategy in vitro in haematopoietic cell lines and in primary JMML cells. These results will need further validation in JMML xenograft models.

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Gene exprssion profile classification predicts clinical outcome in juvenile myelomonocytic leukemia

Project description:Gene expression analysis identified a specific signature of differentially expressed genes discriminating good and poor responders in JMML patients. Gene expression signatures were analyzed on two EWOG patient cohorts of pediatric JMML patients. Keywords: Expression data Class comparison between AML-like vs non-AML-like signatures in JMML patients.

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