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Setbp1 and Ets2-Erg

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Setbp1 and Ets2-Erg UNIVERSITÀ DEGLI STUDI DI MILANO BICOCCA DIPARTIMENTO DI MEDICINA E CHIRURGIA DOTTORATO IN EMATOLOGIA SPERIMENTALE XXVIII CICLO CHARACTERIZATION OF NEW ONCOGENES IDENTIFIED THROUGH NGS-BASED ANALYSIS OF LEUKEMIAS: SETBP1 AND ETS2-ERG Dr. Marco Peronaci Coordinatore: Prof. Carlo Gambacorti Passerini Tutor: Dr.ssa Sara Redaelli Dr. Rocco Piazza Anno Accademico 2015-2016 To my parents Abstract The improvements in sequencing technology led to the development of ‘Next Generation Sequencing’ (NGS) technologies. Several NGS approaches exist. Whole genome sequencing (WGS) and whole exome sequencing (WES) allow the identification of genomic alterations such as small insertions/deletions, point mutations and structural variants. Whole transcriptome sequencing (RNA-Seq) permits to quantify gene expression profiles and to detect alternative splicing and fusion transcripts. Recently, by using WES on atypical chronic myeloid leukemia (aCML) samples, our group identified recurrent mutations in SETBP1 gene [1]; also, by using RNA-Seq on acute myeloid leukemia (AML), we identified a new fusion gene: ETS2-ERG [2]. The aim of this work is to characterize both SETBP1 and ETS2-ERG to gain further insight about their function and role in the pathogenesis of aCML and APL, respectively. In aCML, SETBP1 mutations disrupt a degron binding site, leading to decreased protein degradation. This leads to an increased amount of SETBP1 protein interacting with its natural ligand SET, which in turn acts inhibiting the protein phosphatase 2A (PP2A) oncosuppressor. Interestingly, the SETBP1 mutational cluster affected in aCML is highly conserved and the same mutations were also observed in the Schinzel-Giedion syndrome (SGS). However, the inhibition of the PP2A by SET, the only known interactor of SETBP1, does not explain the phenotype of SGS. To further characterize the role of SETBP1 protein, 293 Flp-In isogenic cellular models expressing the empty vector or the wild type (WT) or mutated (G870S) form of SETBP1 were established. In these models, SETBP1 was fused with a V5 tag. Chromatin immunoprecipitation sequencing experiments (ChIP-Seq) performed against V5 confirmed the binding of SETBP1 to DNA, both for the WT and G870S forms. In addition, RNA-Seq experiments were performed. The comparison between ChIP-Seq and RNA-Seq data has allowed us to identify 130 genes presenting both the binding of SETBP1 to their promoter region and transcriptional upregulation. Together these data suggest a role for SETBP1 as a transcriptional activator. Co-immunoprecipitation (Co- IP) experiments in transiently transfected 293T cells coupled with mass spectrometry (MS) analysis were performed to identify potential interactors of SETBP1. MS analysis led to the identification of the host cell factor 1 (HCF1), a component of the SET1/KMT2A COMPASS-like complex. Independent validation by western blot and fluorescence resonance energy transfer (FRET) confirmed the direct binding of HCF1 to SETBP1. Further independent experiments confirmed the Co-IP of SET1/KMT2A and PHF8 with SETBP1. SET1/KMT2A is a core component of COMPASS-like complex and possesses H3K4 methyltransferase activity, whereas PHF8 possesses H4K20 demethylase activity. Both marks are associated with actively transcribed genes. Taken together, we have shown that SETBP1 protein is able to act as a transcriptional activator recruiting the HCF1/KMT2A/PHF8 complex. In a previous study, comparing cytogenetic analysis and RNA-Seq to detect chromosomal abnormalities on AML patient samples, a new fusion between the ETS2 and ERG genes was reported. The patient carrying this fusion was affected by acute promyelocytic leukemia (APL) and did not respond to therapy with retinoic acid. The role of the ETS2-ERG fusion is not known. To gain insight about the functional role of ETS2-ERG fusion in APL two cellular models were established. HL-60 cells were stable transfected with retroviral empty vector or with a vector carrying the fusion gene. This vector also carries the GFP as a positive selection marker. HL-60 cells carrying the ETS2-ERG fusion treated with retinoic acid showed a decrease in the expression at membrane level of the differentiation marker CD11b. This suggests that the ETS2-ERG fusion is able to impair the differentiation of APL cells upon retinoic acid treatment. Table of content INTRODUCTION ................................................................................................................................ 1 1.2.1 WGS ............................................................................................................................................................8 1.2.2 WES .............................................................................................................................................................9 1.2.3 RNA-Seq ......................................................................................................................................................9 1.2.4 ChIP-Seq ......................................................................................................................................................9 1.3 Hematopoiesis ..................................................................................................................................................10 1.4 Leukemia ..........................................................................................................................................................12 1.5 The 2016 WHO classification of myeloid neoplasm and acute myeloid leukemia ............................................12 1.6 Myeloproliferative neoplasms .........................................................................................................................13 1.7 Myelodysplastic syndromes .............................................................................................................................14 1.8 Myelodysplastic/myeloproliferative neoplasms ..............................................................................................14 1.8.1 Atypical chronic myeloid leukemia (aCML).................................................................................................15 1.8.1.1 Molecular aspects ..............................................................................................................................16 1.8.1.2 SETBP1 ...............................................................................................................................................17 1.9 Acute myeloid leukemia (AML) ........................................................................................................................19 1.9.1 Classification ..............................................................................................................................................20 1.9.2 Acute promyelocytic leukemia (APL) ..........................................................................................................25 1.9.2.1 ETS2-ERG fusion .................................................................................................................................27 AIM ................................................................................................................................................ 30 MATERIALS AND METHODS ............................................................................................................ 32 3.1 Cell Lines ...........................................................................................................................................................33 3.2 SETBP1 plasmids and cell lines generation .......................................................................................................33 3.3 Chromatin Immunoprecipitation sequencing (ChIP-Seq) .................................................................................34 3.4 Co-immunoprecipitation (Co-IP) .......................................................................................................................35 3.5 Proteomics data analysis ..................................................................................................................................36 3.6 Immunofluorescence microscopy .....................................................................................................................37 3.7 Acceptor photobleaching Resonance Energy Transfer (FRET) ..........................................................................37 3.8 RNA-Seq ...........................................................................................................................................................38 3.9 Differential expression analysis ........................................................................................................................38 3.10 Quantitative Real-Time PCR (qRT-PCR)...........................................................................................................38 3.11 MECOM analysis .............................................................................................................................................39 3.12 AML patients and ETS2-ERG fusion screening ................................................................................................39 3.13 HL-60 cells differentiation assay and flow cytometric analysis ......................................................................41 RESULTS ........................................................................................................................................
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