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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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EZH2 mutations can be detected in 23% of PICALM-MLLT10 (CALM-AF10) positive acute leukemias

ABSTRACT: Interest focuses on genes encoding histone demethylases in hematologic malignancies, such as EZH2 (enhancer of zeste homolog 2). EZH2 mutations were recurrently observed in lymphomas and chronic myeloid malignancies, but data in acute leukemias are limited. We investigated 13 PICALM-MLLT10 (=CALM-AF10) rearranged acute leukemia predominantly of T-lineage (7 m/6 f; 6–53 years) by deep-sequencing for EZH2mut and identified 3 (23%) EZH2mut carriers: one splice site mutation in exon 14, while two patients had missense mutations in the D1 region of exon 5 which interacts with different DNA methyltransferase genes (but no DNMT3Amut was detected in the 13 PICALM-MLLT10-positive patients). In contrast, no EZH2mut was found in an independent cohort of 12 PICALM-MLLT10-negative T-ALL. Gene expression profiling revealed increased expression of genes with a role for transcription or intracellular transport processes in the PICALM-MLLT10-positive cases. The frequent occurrence of EZH2mut in PICALM-MLLT10-positive malignancies emphasizes a cooperative effect in acute leukemias. 29 patients analyzed with gene expression microarrays.

ORGANISM(S): Homo sapiens

SUBMITTER: Hans-Ulrich Klein

PROVIDER: E-GEOD-30599 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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EZH2 mutations can be detected in 23% of PICALM-MLLT10 (CALM-AF10) positive acute leukemias

Project description:Interest focuses on genes encoding histone demethylases in hematologic malignancies, such as EZH2 (enhancer of zeste homolog 2). EZH2 mutations were recurrently observed in lymphomas and chronic myeloid malignancies, but data in acute leukemias are limited. We investigated 13 PICALM-MLLT10 (=CALM-AF10) rearranged acute leukemia predominantly of T-lineage (7 m/6 f; 6–53 years) by deep-sequencing for EZH2mut and identified 3 (23%) EZH2mut carriers: one splice site mutation in exon 14, while two patients had missense mutations in the D1 region of exon 5 which interacts with different DNA methyltransferase genes (but no DNMT3Amut was detected in the 13 PICALM-MLLT10-positive patients). In contrast, no EZH2mut was found in an independent cohort of 12 PICALM-MLLT10-negative T-ALL. Gene expression profiling revealed increased expression of genes with a role for transcription or intracellular transport processes in the PICALM-MLLT10-positive cases. The frequent occurrence of EZH2mut in PICALM-MLLT10-positive malignancies emphasizes a cooperative effect in acute leukemias.

2011-11-25 | GSE30599 | GEO

EZH2 mutations can be detected in 23% of PICALM-MLLT10 (CALM-AF10) positive acute leukemias

2011-11-25 | GSE30599 | GEO

Homo sapiens

Project description:EZH2 mutations can be detected in 23% of PICALM-MLLT10 (CALM-AF10) positive acute leukemias

| PRJNA144567 | ENA

MLLT10 gene recombinations in pediatric T-Acute Lymphoblastic Leukemia

Project description:MLLT10, a 24 exons gene at 10p12, is known in leukemogenesis as partner of MLL or PICALM and recently NAP1L1. We identified HNRNPH1 and DDX3X, genes involved in RNA processing, as new MLLT10 partners in 2 cases of pediatric NOTCH1 positive T-ALL. HNRNPH1/5q35 encodes for a member of the ubiquitously expressed heterogeneous nuclear ribonucleoprotein (hnRNP) subfamily of RNA binding protein. DDX3X/Xp11.3, belongs to the big family of RNA helicases with a DEAD box domain. Whole genome analysis by SNPs and Combined Interphase FISH (CI-FISH) identified different co-operating lesions in the two cases. Fusion isoforms were found in both cases: interestingly all fusions retained the OM-LZ domain of MLLT10 that is needed to induce Acute Myeloid Leukemia in mice. Gene expression profiling (GEP) of the two new MLLT10 fusions was similar to PICALM-MLLT10 positive but differed from other HOXA positive T-ALL, suggesting MLLT10 fusions share a common leukemogenic pathway. Clinical data indicate relative good prognosis in T-ALL with MLLT10 variants. This submission represents the gene expression component of the study [For privacy reasons, SNP data will not be deposited].

2013-07-03 | E-GEOD-42765 | biostudies-arrayexpress

MLLT10 gene recombinations in pediatric T-Acute Lymphoblastic Leukemia

2013-07-03 | GSE42765 | GEO

MLLT10 gene recombinations in pediatric T-Acute Lymphoblastic Leukemia

2013-07-03 | GSE42765 | GEO

Peturbation of PICALM Levels Alters Cellular Cholesterol Metabolism

Project description:PICALM (Phosphatidyl Inositol Clathrin Assembly Lymphoid Myeloid protein) is a ubiquitously expressed protein that plays a role in clathrin-mediated endocytosis. PICALM also affects the internalization of SNAREs and modulates macroautophagy. Chromosomal translocations that result in the fusion of PICALM to heterologous proteins cause leukemias, and genome-wide association studies have linked Single Nucleotide Polymorphisms (SNPs) of PICALM to Alzheimer’s disease. To obtain insight into the biological role of PICALM, we performed gene expression studies of PICALM-deficient and PICALM-expressing cells. Pathway analysis demonstrated that PICALM expression influences the expression of genes that encode proteins involved in cholesterol biosynthesis and lipoprotein uptake. GC-MS studies indicated that loss of PICALM increases total cholesterol pool size. Isotopic labeling studies revealed that loss of PICALM alters cholesterol homeostasis via increased scavenging of cholesterol. Measurement of LDL receptor endocytosis further showed that PICALM deficient cells express higher LDLR levels resulting in higher lipoprotein internalization. These findings suggest that PICALM is required for cellular cholesterol homeostasis and point to a novel mechanism by which PICALM alterations may contribute to disease.

2015-06-17 | GSE64855 | GEO

Peturbation of PICALM Levels Alters Cellular Cholesterol Metabolism

2015-06-17 | E-GEOD-64855 | biostudies-arrayexpress

Epigenetic extinction of fetal programming promotes leukemia stem cell activity

Project description:Acute leukemias are aggressive malignancies of developmentally arrested hematopoietic progenitors. We sought here to explore the possibility that changes in hematopoietic stem/progenitor cells during aging might alter the biology of leukemias arising from this tissue compartment. Using a mouse model of acute T-cell leukemia, we found that leukemias generated from fetal liver (FL) and adult bone marrow (BM) differed dramatically in their leukemia stem cell activity with FL leukemias showing markedly reduced serial transplantability as compared to BM leukemias. We present evidence that this difference is due to NOTCH1-driven autocrine IGF1 signaling which is active in FL cells, but restrained in BM cells by EZH2-dependent H3K27 trimethylation. Further, we confirmed this mechanism is operative in human disease, and show that enforced IGF1 signaling effectively limits leukemia stem cell activity. These findings demonstrate that resurrecting dormant fetal programs in adult cells may represent an alternate therapeutic approach in human cancer.

2018-09-27 | GSE118308 | GEO

Contrasting stage-dependent requirements during AML evolution identify EZH2 as a therapeutic target in AML

Project description:Epigenetic regulators are commonly mutated in cancer. Activating mutations and overexpression of the lysine histone methyltransferase EZH2 occur in lymphoma and other malignancies, while loss-of-function mutations are found in myeloid malignancies. We study this apparent contradiction, examining the importance of cellular context for Ezh2 loss during the evolution of a single malignancy, Acute Myeloid Leukemia (AML). Remarkably, we observe diametrically opposite functions for Ezh2 at early and late stages during the evolution of leukemias generated by different AML-associated fusion-oncogenes. During disease maintenance we demonstrate that Ezh2 functions as an oncogene that may be therapeutically targeted. In contrast, Ezh2 acts as a tumour suppressor during AML induction and loss-of-function EZH2 mutations occur early in AML patient samples and confer a poor prognosis. Integrated genomic analysis demonstrates that different expression programmes are de-repressed during AML induction and maintenance following Ezh2 loss. During disease induction, Ezh2 loss de-represses a subset of bivalent promoters that resolve towards gene activation, inducing a feto-oncogene programme including genes such as Plag1, whose overexpression phenocopies Ezh2 loss to accelerate AML induction in mouse models. Our data highlight the importance of cellular context and phase of disease evolution for Ezh2 function. Moreover, we further identify EZH2 as a potential target in AML, whilst providing reassurance of the safety of this therapeutic strategy.

2019-03-07 | GSE112724 | GEO

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