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Identification and functional characterization of the miRNA-gene regulatory network in chronic myeloid leukemia lineage negative cells.

ABSTRACT: Chronic myeloid leukemia (CML) is maintained by leukemic stem cells (LSCs) which are resistant to the existing TKI therapy. Hence a better understanding of the CML LSCs is necessary to eradicate these cells and achieve complete cure. Using the miRNA-gene interaction networks from the CML lin(-) cells we identified a set of up/down-regulated miRNAs and corresponding target genes. Association studies (Pearson correlation) from the miRNA and gene expression data showed that miR-1469 and miR-1972 have significantly higher number of target genes, 75 and 50 respectively. We observed that miR-1972 induces G2-M cell cycle arrest and miR-1469 moderately arrested G1 cell cycle when overexpressed in KCL22 cells. We have earlier shown that a combination of imatinib and JAK inhibitor I can significantly bring down the proliferation of CML lineage negative cells. Here we observed that imatinib and JAK inhibitor I combination restored the expression pattern of the down-regulated miRNAs in primary CML lin(-) cells. Thus effective manipulation of the deregulated miRNAs can restore the miRNA-mRNA networks that can efficiently inhibit CML stem and progenitor cells and alleviate the disease.

SUBMITTER: Agatheeswaran S

PROVIDER: S-EPMC5009428 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Identification and functional characterization of the miRNA-gene regulatory network in chronic myeloid leukemia lineage negative cells.

Agatheeswaran S S Pattnayak N C NC Chakraborty S S

Scientific reports 20160902

Chronic myeloid leukemia (CML) is maintained by leukemic stem cells (LSCs) which are resistant to the existing TKI therapy. Hence a better understanding of the CML LSCs is necessary to eradicate these cells and achieve complete cure. Using the miRNA-gene interaction networks from the CML lin(-) cells we identified a set of up/down-regulated miRNAs and corresponding target genes. Association studies (Pearson correlation) from the miRNA and gene expression data showed that miR-1469 and miR-1972 ha ...[more]

PMID: 27586591

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Project description:IntroductionCircRNA is closely correlated with a wide variety of processes of acute myeloid leukemia (AML), whereas the novel circRNAs, their molecular mechanism and the specific function they played in AML should be explored in depth.MethodsThe microarray chip data of AML patients and normal samples in the Gene Expression Omnibus (GEO) database were selected to differentially expressed (DE) circRNA, miRNA, and mRNA genes. The miRNA gene was the intersection of the circRNA target gene predicted using CSCD and the miRNA gene screened from AML patients, while the mRNA gene was the intersection of the target gene mRNA of miRNA predicted using miRanda and miRTarBase software and the mRNA gene screened from AML patients. The hub mRNAs related to survival were further screened through Cox proportional hazard regression. CircRNA/miRNA/mRNA interaction network was constructed by using Cytoscape software.10 circRNAs and 6 miRNAs in bone marrow mononuclear cells (BMMNCs) of AML patients (n=43) and healthy controls (n=35) were determined by RT-qPCR. Correlations between them were analyzed by Pearson correlation coefficient.Results10 circRNAs, 6 miRNAs, and 33 mRNAs were identified. Subsequently, the network of circRNAs, miRNAs, and hub genes was built using Cystoscope. Four key circRNAs, seven hub genes and their regulatory pathways were identified. The result of RT-qPCRs showed that hsa_circ_0009581 and hsa_circ_0005273 were significantly upregulated in AML patients while hsa_circ_0000497 and hsa_circ_0001947 were significantly downregulated. Hsa-miR-150-5p was significantly downregulated; hsa-miR-454-3p was upregulated in AML patients. Hsa_circ_0009581 and hsa-miR-150-5p; hsa_ circ_0001947 and hsa-miR-454-3p were inversely correlated using Pearson's correlation coefficient.ConclusionThis study suggests that differentially expressed circRNAs take on a critical significance to AML development and may be the effective therapeutic targets. We suppose that hsa_circ_0009581 promotes leukemia development through hsa-miR-150-5p and hsa_circ_0001947 through hsa-miR-454-3p. hsa_circ_0001947 and hsa_circ_0009581 may provide new directions in the pathogenesis of AML.

Project description:BACKGROUND: Molecular characterization of the FMS-like tyrosine kinase 3 receptor (FLT3) in cytogenetically normal acute myeloid leukemia (AML) has recently been incorporated into clinical guidelines based on correlations between FLT3 internal tandem duplications (FLT3-ITD) and decreased disease-free and overall survival. These mutations result in constitutive activation of FLT3, and FLT3 inhibitors are currently undergoing trials in AML patients selected on FLT3 molecular status. However, the transient and partial responses observed suggest that FLT3 mutational status alone does not provide complete information on FLT3 biological activity at the individual patient level. Examination of variation in cellular responsiveness to signaling modulation may be more informative. METHODOLOGY/PRINCIPAL FINDINGS: Using single cell network profiling (SCNP), cells were treated with extracellular modulators and their functional responses were quantified by multiparametric flow cytometry. Intracellular signaling responses were compared between healthy bone marrow myeloblasts (BMMb) and AML leukemic blasts characterized as FLT3 wild type (FLT3-WT) or FLT3-ITD. Compared to healthy BMMb, FLT3-WT leukemic blasts demonstrated a wide range of signaling responses to FLT3 ligand (FLT3L), including elevated and sustained PI3K and Ras/Raf/Erk signaling. Distinct signaling and apoptosis profiles were observed in FLT3-WT and FLT3-ITD AML samples, with more uniform signaling observed in FLT3-ITD AML samples. Specifically, increased basal p-Stat5 levels, decreased FLT3L induced activation of the PI3K and Ras/Raf/Erk pathways, decreased IL-27 induced activation of the Jak/Stat pathway, and heightened apoptotic responses to agents inducing DNA damage were observed in FLT3-ITD AML samples. Preliminary analysis correlating these findings with clinical outcomes suggests that classification of patient samples based on signaling profiles may more accurately reflect FLT3 signaling deregulation and provide additional information for disease characterization and management. CONCLUSIONS/SIGNIFICANCE: These studies show the feasibility of SCNP to assess modulated intracellular signaling pathways and characterize the biology of individual AML samples in the context of genetic alterations.

Project description:The first treatment of chronic myeloid leukemia (CML) included spleen x-radiation and conventional drugs, mainly Busulfan and Hydroxyurea. This therapy improved the quality of life during the chronic phase of the disease, without preventing nor significantly delaying the progression towards advanced phases. The introduction of allogeneic stem cell transplantation (alloSCT) marked the first important breakthrough in the evolution of CML treatment, because about 50% of the eligible patients were cured. The second breakthrough was the introduction of human recombinant interferon-alfa, able to achieve a complete cytogenetic remission in 15% to 30% of patients, with a significant survival advantage over conventional chemotherapy. At the end of the last century, about 15 years ago, all these treatments were quickly replaced by a class of small molecules targeting the tyrosine kinases (TK), which were able to induce a major molecular remission in most of the patients, without remarkable side effects, and a very prolonged life-span. The first approved TK inhibitor (TKI) was Imatinib Mesylate (Glivec or Gleevec, Novartis). Rapidly, other TKIs were developed tested and commercialized, namely Dasatinib (Sprycel, Bristol-Myers Squibb), Nilotinib (Tasigna, Novartis), Bosutinib (Busulif, Pfizer) and Ponatinib (Iclusig, Ariad). Not all these compounds are available worldwide; some of them are approved only for second line treatment, and the high prices are a problem that can limit their use. A frequent update of treatment recommendations is necessary. The current treatment goals include not only the prevention of the transformation to the advanced phases and the prolongation of survival, but also a length of survival and of a quality of life comparable to that of non-leukemic individuals. In some patient the next ambitious step is to move towards a treatment-free remission. The CML therapy, the role of alloSCT and the promising experimental strategies are reviewed in the context of the new therapeutic goals.

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Identification and functional characterization of the miRNA-gene regulatory network in chronic myeloid leukemia lineage negative cells.

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Identification and functional characterization of the miRNA-gene regulatory network in chronic myeloid leukemia lineage negative cells.

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