ZBTB7A prevents RUNX1-RUNX1T1 dependent clonal expansion of human hematopoietic progenitor cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE140472 | GEO | 2020/04/07
REPOSITORIES: GEO
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Project description:Activating CSF3R mutations are recurrent in AML with t(8;21) translocation. However, the nature of oncogenic collaboration between alterations of CSF3R and the t(8;21) associated RUNX1-RUNX1T1 fusion remains unclear. In CD34+ hematopoietic stem and progenitor cells from healthy donors, double oncogene expression led to a clonal advantage, increased self-renewal potential, as well as blast-like morphology and distinct immunophenotype. Gene expression profiling revealed hedgehog-signaling as a potential mechanism, with upregulation of GLI2 constituting a putative pharmacological target. Both primary hematopoietic cells and the t(8;21) positive AML cell line SKNO-1 showed increased sensitivity to the GLI-inhibitor GANT61 when expressing CSF3R T618I. Our findings suggest that during leukemogenesis the RUNX1-RUNXT1 fusion and CSF3R mutation act in a synergistic manner to alter hedgehog signaling which can be exploited therapeutically.
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Project description:Activating CSF3R mutations are recurrent in AML with t(8;21) translocation. However, the nature of oncogenic collaboration between alterations of CSF3R and the t(8;21) associated RUNX1-RUNX1T1 fusion remains unclear. In CD34+ hematopoietic stem and progenitor cells from healthy donors, double oncogene expression led to a clonal advantage, increased self-renewal potential, as well as blast-like morphology and distinct immunophenotype. Gene expression profiling revealed hedgehog-signaling as a potential mechanism, with upregulation of GLI2 constituting a putative pharmacological target. Both primary hematopoietic cells and the t(8;21) positive AML cell line SKNO-1 showed increased sensitivity to the GLI-inhibitor GANT61 when expressing CSF3R T618I. Our findings suggest that during leukemogenesis the RUNX1-RUNXT1 fusion and CSF3R mutation act in a synergistic manner to alter hedgehog signaling which can be exploited therapeutically.
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Project description:ZBTB7A prevents RUNX1-RUNX1T1 dependent clonal expansion of human hematopoietic progenitor cells
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Project description:We performed genome wide miRNA expression analysis to investigate the ability of miRNAs in predicting leukemia relapse from 33 t(8;21) pediatric AMLs at diagnosis divided into a training and a validation cohort. COX regression analysis and ROC curves were used to identify a powerful miRNA signature able to predict relapse in t(8;21) AML patients. miRNA profiling showed that patients with high- or low- risk of relapse had different expression profiles. We support the role of microRNAs in modulating the prognosis of t(8;21)-AML and the use of a miRNA expression signature at diagnosis to better define standard risk cases in pediatric AML.
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Project description:In acute myeloid leukemia (AML) non-random clonal chromosome aberrations are detectable in ~55% of adults with AML. Translocation t(8;21)(q22;q22) resulting in the 5'RUNX1/3'RUNX1T1 fusion gene occurs in ~8% of acute myeloid leukemia (AML) cases. Also, insertions ins(8;21) and ins(21;8) have been described that show a broad heterogeneity at the molecular level with inserted fragment sizes ranging from 2.4 to 44 Mb. Microarray-based comparative genomic hybridization (arrayCGH) in 49 intermediate-risk AML and RT-PCR-based screening in 532 AML cases allowed the detection of ins(21;8)/ins(8;21) in three cases; arrayCGH and subsequent RT-PCR revealed an ~0.5 Mb sized inserted fragment generating the 5'RUNX1/3'RUNX1T1 fusion gene in one case with a submicroscopic ins(21;8)(q22;q22q22) whereas the other two cases were identified by banding analysis and RT-PCR, respectively. Gene expression profiling (GEP) and a detailed review of the literature highlighted similar biological features of AML cases with ins(21;8)/ins(8;21) and t(8;21)(q22;q22). Our study demonstrates the potential of high-resolution array-based analysis and GEP and provides further evidence that AML with insertions generating the 5'RUNX1/3'RUNX1T1 fusion not only biologically resemble the t(8;21)(q22;q22) AML subgroup, but might also share their prognostically favorable clinical behavior. Thus, similar treatment options should be considered in these patients. An all pairs experiment design type is where all labeled extracts are compared to every other labeled extract.
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Project description:In acute myeloid leukemia (AML) non-random clonal chromosome aberrations are detectable in ~55% of adults with AML. Translocation t(8;21)(q22;q22) resulting in the 5'RUNX1/3'RUNX1T1 fusion gene occurs in ~8% of acute myeloid leukemia (AML) cases. Also, insertions ins(8;21) and ins(21;8) have been described that show a broad heterogeneity at the molecular level with inserted fragment sizes ranging from 2.4 to 44 Mb. Microarray-based comparative genomic hybridization (arrayCGH) in 49 intermediate-risk AML and RT-PCR-based screening in 532 AML cases allowed the detection of ins(21;8)/ins(8;21) in three cases; arrayCGH and subsequent RT-PCR revealed an ~0.5 Mb sized inserted fragment generating the 5'RUNX1/3'RUNX1T1 fusion gene in one case with a submicroscopic ins(21;8)(q22;q22q22) whereas the other two cases were identified by banding analysis and RT-PCR, respectively. Gene expression profiling (GEP) and a detailed review of the literature highlighted similar biological features of AML cases with ins(21;8)/ins(8;21) and t(8;21)(q22;q22). Our study demonstrates the potential of high-resolution array-based analysis and GEP and provides further evidence that AML with insertions generating the 5'RUNX1/3'RUNX1T1 fusion not only biologically resemble the t(8;21)(q22;q22) AML subgroup, but might also share their prognostically favorable clinical behavior. Thus, similar treatment options should be considered in these patients.
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Project description:Single-cell RNA sequencing analysis of RUNX1-RUNX1T1(9a) transformed c-kit positive cells with (Kat2a WT) and without Kat2a (Kat2a NULL). Lineage negative bone marrow cells were collected from Kat2a fl/fl Mx1-Cre-/- and Kat2a fl/fl Mx1-Cre +/- animals after pIpC treatment and transduced with RUNX1-RUNX1T1(9a) expressing retrovirus (reported by GFP expression). Cells were injected into irradiated C57BL6 mice and GFP positive c-Kit positive bone marrow cells collected 2 and 4 months after transplantation. Cells were processed for single-cell RNA sequencing library preparation (10X chromium single cell) and next gene sequencing following 10X genomics v2 protocol.
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Project description:The fusion oncogene RUNX1/RUNX1T1 encodes an aberrant transcription factor, which plays a key role in the initiation and maintenance of acute myeloid leukaemia. In this study we comprehensively identify and characterize splicing events associated with RUNX1/RUNX1T1. We show that this oncogene is a regulator of the alternative RNA splicing in leukaemic cells. We found two principal mechanisms underlying changes in the production of RNA isoforms: (i) RUNX1/RUNX1T1-mediated regulation of alternative transcription start sites selection, and (ii) direct or indirect control of the expression of the genes encoding splicing factors. The first mechanism leads to the expression of RNA isoforms with alternative structure of the 5’-UTR regions. The second mechanism generates alternative transcripts with new junctions between internal cassettes and constitutive exons. We also show that RUNX1/RUNX1T1-mediated differential splicing affects several functional groups of genes and produces proteins with unique conserved domain structures. In summary, this study reveals a novel layer of transcriptome re-organization in leukaemia by an aberrant transcriptional regulator.
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Project description:Zinc finger and BTB domain containing transcription repressor ZBTB7A has been recently reported as a tumor suppressor who plays important functions to prevent the progression of prostate cancer. However, the chromatin activity of ZBTB7A in prostate cancer cells remain unclear. In order to identify the cistrome and transcriptome of ZBTB7A, we performed ZBTB7A ChIP-seq in VCaP cells and RNA-seq in VCaP cells transfected with siRNA targeting ZBTB7A or non-targeting control, respectively (cells were grown in full serum). By using combined ChIP-seq and RNA-seq analyses in VCaP cells, we have precisely mapped the ZBTB7A binding sites and identified a subset of genes that are directly repressed by ZBTB7A. To study the chromatin interaction of ZBTB7A with androgen receptor (AR), we also performed ChIP-seq of ZBTB7A in VCaP cells stimulated with 10 nM DHT for 4 hours versus vehicle control (cells were hormone-depleted prior to DHT stimulation). Our results show that ZBTB7A binding is increased by androgen at AR and ZBTB7A overlapping sites.
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