Unknown,Transcriptomics,Genomics,Proteomics

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Expression patterns of microRNAs associated with CML phases and their disease related targets

ABSTRACT: Background MicroRNAs are important regulators of transcription in hematopoiesis. Their expression deregulations were described in association with pathogenesis of some hematological malignancies. This study provides integrated microRNA expression profiling at different phases of chronic myeloid leukemia (CML) with the aim to select CML specific miRNAs and find new possible biomarkers. The functions of in silico filtered targets are in this report annotated and discussed in relation to CML pathogenesis. Results Using microarrays we identified differential expression profiles of 49 miRNAs in CML patients at diagnosis, in hematological relapse, therapy failure, blast crisis and major molecular response. The expression deregulation of miR-150, miR-20a, miR-17, miR-19a, miR-103, miR-144, miR-155, miR-181a, miR-221 and miR-222 in CML was confirmed by real-time quantitative PCR and in silico analyses identified targeted genes of these miRNAs encoding proteins that are involved in cell cycle, growth inhibition, MAPK, ErBb, transforming growth factor beta and p53 signaling pathways that are related to CML. Validated miR-150 decreased levels were detected in patients at diagnosis, in blast crisis and 67% of hematological relapses and showed significant negative correlation with miR-150 proved target MYB and with BCR-ABL transcript level. Conclusions This study revealed microRNAs that may be related to the CML pathogenesis and may reflect transformation from chronic to accelerated phases. The obtained expression patterns in peripheral blood total leukocytes during the course of CML suggest specific miRNAs as possible biomarkers. The annotated functions of in silico filtered targets of selected miRNAs outline mechanisms whereby microRNAs may be involved in CML pathogenesis. Twenty four patient samples of total leukocytes from peripheral blood were used to prepare pools representing different CML phases for microarray analysis: diagnosis (n=5, Dg), major molecular response (n=5, MMR), therapy failure (n=5, TF), hematological relapse (n=5, Hr), and blast crisis (n=4, BC). Eleven healthy donors of age median 60 (range 45 - 78) and man/woman ratio 3/2 following CML incidence were used to create a control pool.

ORGANISM(S): Homo sapiens

SUBMITTER: Silvia Rueberg

PROVIDER: E-GEOD-26260 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression patterns of microRNAs associated with CML phases and their disease related targets.

Machová Poláková Kateřina K Lopotová Tereza T Klamová Hana H Burda Pavel P Trněný Marek M Stopka Tomáš T Moravcová Jana J

Molecular cancer 20110418

<h4>Background</h4>MicroRNAs are important regulators of transcription in hematopoiesis. Their expression deregulations were described in association with pathogenesis of some hematological malignancies. This study provides integrated microRNA expression profiling at different phases of chronic myeloid leukemia (CML) with the aim to identify microRNAs associated with CML pathogenesis. The functions of in silico filtered targets are in this report annotated and discussed in relation to CML pathog ...[more]

PMID: 21501493

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Project description:Our objective is to decipher a miRNA expression signature associated with Chronic myeloid leukemia (CML), with or without Imatinib or Dasatinib and compared to normal blood leukocytes, and to determine potential target genes and signaling pathways affected by these signature miRNAs. Background/Aims: MicroRNAs (miRNAs) are short non-coding regulatory RNAs that control gene expression and play an important role in cancer development and progression. However, little is known about the role of miRNAs in chronic myeloid leukemia (CML). Our objective is to decipher a miRNA expression signature associated with CML and to determine potential target genes and signaling pathways affected by these signature miRNAs. Results: Using miRNA microarrays we characterized the miRNAs expression profile of K562 cells in reference to healthy blood. We also looked into the expression profile of K562 cells treated with imatinib or dasatinib. We identified a miRNA signature that distinguishes K562 cells from healthy blood that included downregulation of miRNAs such as miR-31, miR-34a, miR-143, miR-145, miR-155, miR-196b and miR-564 and upregulation of miR-128. We also identified a miRNA signature that distinguishes untreated K562 cells from the treated ones that included downregulation of miRNAs such as miR-128 and upregulation of miR-564. Results: Using miRNA microarrays we characterized the miRNAs expression profile of K562 cells in reference to healthy blood. We also looked into the expression profile of K562 cells treated with imatinib or dasatinib. We identified a miRNA signature that distinguishes K562 cells from healthy blood that included downregulation of miRNAs such as miR-31, miR-34a, miR-143, miR-145, miR-155, miR-196b and miR-564 and upregulation of miR-128. We also identified a miRNA signature that distinguishes untreated K562 cells from the treated ones that included downregulation of miRNAs such as miR-128 and upregulation of miR-564. We next analyzed predicted targets and affected pathways of the deregulated miRNAs. Reassuringly, the analysis identified CML as the main disease associated with these miRNAs. MAPK, TGF-beta and Wnt were the main molecular pathways related with these expression patterns. Utilizing Venn diagrams we found appreciable overlap between the CML-related miRNAs and the MAPK and TGF-beta signaling pathways and focal adhesion-related miRNAs. Conclusions: The miRNAs identified in this study might offer a pivotal role in CML. Nevertheless, while these data point to a central disease, the precise molecular pathway/s targeted by these miRNAs is variable implying a high level of complexity of miRNA target selection and regulation. These deregulated miRNAs highlight new candidate gene targets allowing for a better understanding of the molecular mechanism underlying the development of CML, and propose possible new avenues for therapeutic treatment. MiRNA profiling of CML: With the objective of deciphering a potential miRNA expression signature associated with CML, we analyzed the miRNAs expression profile of K562 in reference to a pool of 3 healthy blood samples using an miRNA-based microarray chip assay. In addition, to search for Bcr-Abl-dependent or Src-dependant miRNA expression patterns, K562 cells were treated or not with imatinib or with dasatinib to inhibit Bcr-Abl tyrosine kinase activity or Bcr-Abl and Src tyrosine kinase activity, respectively. In order to validate the microarray data and to ensure that the variability observed among samples was not technical, we carried out Taqman miRNA quantitative real-time PCR analysis (Applied Biosystems, USA) on miRNAs that we find to be most relevant, according to bioinformatics analysis (see below) and published data.

Project description:MiR-142 is dynamically expressed and plays a regulatory role in hematopoiesis. Based on the simple observation that miR-142 levels are significantly lower in CD34+CD38- cells from blast crisis (BC) chronic myeloid leukemia (CML). CML patients compared with chronic phase (CP) CML patients (p=0.002), we hypothesized that miR-142 deficit plays a role in BC transformation. To test this hypothesis, we generated a miR-142 KO BCR-ABL (i.e., miR-142−/−BCR-ABL) mouse by crossing a miR-142−/− mouse with a miR-142+/+BCR-ABL mouse. While the miR-142+/+BCR-ABL mice developed and died of CP CML, the miR-142−/−BCR-ABL mice developed a BC-like phenotype in the absence of any other acquired gene mutations and died significantly sooner than miR-142+/+BCR-ABL CP controls (p=0.001). Leukemic stem cell (LSC)-enriched Lineage-Sca-1+c-Kit+ cells (LSKs) from diseased miR-142−/−BCR-ABL mice transplanted into congenic recipients, recapitulated the BC features thereby suggesting stable transformation of CP-LSCs into BC-LSCs in the miR-142 KO CML mouse. Single cell (sc) RNA-seq profiling showed that miR-142 deficit changed the cellular landscape of the miR-142−/−BCR-ABL LSKs compared with miR-142+/+BCR-ABL LSKs with expansion of myeloid-primed and loss of lymphoid-primed factions. Bulk RNA-seq analyses along with unbiased metabolomic profiling and functional metabolic assays demonstrated enhanced fatty acid β-oxidation (FAO) and oxidative phosphorylation (OxPhos) in miR-142−/−BCR-ABL LSKs vs miR-142+/+BCR-ABL LSKs. MiR-142 deficit enhanced FAO in miR-142−/−BCR-ABL LSKs by increasing the expression of CPT1A and CPT1B, that controls the cytosol-to-mitochondrial acyl-carnitine transport, a critical step in FAO. MiR-142 deficit also enhanced OxPhos in miR-142−/−BCR-ABL LSKs by increasing mitochondrial fusion and activity. As the homeostasis and activity of LSCs depend on higher levels of these oxidative metabolism processes, we then postulate that miR-142 deficit is a potentially druggable target for BC-LSCs. To this end, we developed a novel CpG-miR-142 mimic oligonucleotide (ODN; i.e., CpG-M-miR-142) that corrected the miR-142 deficit and alone or in combination with a tyrosine kinase inhibitor (TKI) significantly reduced LSC burden and prolonged survival of miR-142−/−BCR-ABL mice. The results from murine models were validated in BC CD34+CD38- primary blasts and patient-derived xenografts (PDXs). In conclusion, an acquired miR-142 deficit sufficed in transforming CP-LSCs into BC-LSCs, via enhancement of bioenergetic oxidative metabolism in absence of any additional gene mutations, and likely represent a novel therapeutic target in BC CML.

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Expression patterns of microRNAs associated with CML phases and their disease related targets

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Expression patterns of microRNAs associated with CML phases and their disease related targets.

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