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Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL

ABSTRACT: The TLX1 and TLX3 transcription factor oncogenes play an important role in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL)1,2. Here we used reverse engineering of global transcriptional networks to decipher the oncogenic regulatory circuit controlled by TLX1 and TLX3. This Systems Biology analysis defined TLX1 and TLX3 as master regulators of an oncogenic transcriptional circuit governing T-ALL. Notably, network structure analysis of this hierarchical network identified RUNX1 as an important mediator of TLX1 and TLX3 induced T-ALL, and predicted a tumor suppressor role for RUNX1 in T-cell transformation. Consistent with these results, we identified recurrent somatic loss of function mutations in RUNX1 in human T-ALL. Overall, these results place TLX1 and TLX3 atop of an oncogenic transcriptional network controlling leukemia development, demonstrate power of network analysis to identify key elements in the regulatory circuits governing human cancer and identify RUNX1 as a tumor suppressor gene in T-ALL. This SuperSeries is composed of the following subset Series: GSE33539: Expression data obtained from ALLSIL cell line GSE33540: Expression data obtained from HPBALL cell line GSE33549: Expression data from mouse T-cell lymphomas

ORGANISM(S): Mus musculus

SUBMITTER: Adolfo Ferrando

PROVIDER: E-GEOD-33550 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression data obtained from HPBALL cell line

Project description:The experiment was designed in order to knock down the expression of TLX3 gene in T-ALL cell line We used microarrays to identify the gene expression signatures associated with TLX3 knock down in HPBALL HPBALL cell lines were infected with pLKO.1-shTLX3 and pLKO.1-luc control lentivirus. After 5 days of puromycin selection cells were collected and RNA was extracted in order to analyze the global changes in gene expression by Affymetrix U133 Plus 2 array.

2011-11-08 | E-GEOD-33540 | biostudies-arrayexpress

Expression data obtained from ALLSIL cell line

Project description:The experiment was designed in order to knock down the expression of TLX1 gene in T-ALL cell line We used microarrays to identify the gene expression signatures associated with TLX1 knock down in ALLSIL ALLSIL cell lines were infected with pLKO.1-shTLX1 and pLKO.1-luc control lentivirus. After 5 days of puromycin selection cells were collected and RNA was extracted in order to analyze the global changes in gene expression by Affymetrix U133 Plus 2 array.

2011-11-08 | E-GEOD-33539 | biostudies-arrayexpress

Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL

Project description:The TLX1 and TLX3 transcription factor oncogenes play an important role in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL)1,2. Here we used reverse engineering of global transcriptional networks to decipher the oncogenic regulatory circuit controlled by TLX1 and TLX3. This Systems Biology analysis defined TLX1 and TLX3 as master regulators of an oncogenic transcriptional circuit governing T-ALL. Notably, network structure analysis of this hierarchical network identified RUNX1 as an important mediator of TLX1 and TLX3 induced T-ALL, and predicted a tumor suppressor role for RUNX1 in T-cell transformation. Consistent with these results, we identified recurrent somatic loss of function mutations in RUNX1 in human T-ALL. Overall, these results place TLX1 and TLX3 atop of an oncogenic transcriptional network controlling leukemia development, demonstrate power of network analysis to identify key elements in the regulatory circuits governing human cancer and identify RUNX1 as a tumor suppressor gene in T-ALL. This SuperSeries is composed of the SubSeries listed below.

2011-11-08 | GSE33550 | GEO

H3K27me3 ChIP-on-chip in T-ALL

Project description:Relative H3K27me3 enrichment, assessed by ChIP-on-chip, in two TLX positive and two TLX negative T Acute Lymphoblastique Leukemia (T-ALL) samples. Acute lymphoblastic leukemias (ALLs) are characterized by multi-step oncogenic processes leading to cell differentiation arrest and proliferation. Specific abrogation of maturation blockage constitutes a promising therapeutic option in cancer, which requires precise understanding of the underlying molecular mechanisms. We show that the cortical thymic maturation arrest in T-lineage ALL that over-express TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of the T cell receptor (TCR) alpha enhanceosome activity and blocked TCR-Jalpha rearrangement. TLX1/TLX3 abrogation or enforced TCRalpha/beta expression leads to TCRalpha rearrangement and apoptosis. Importantly, the auto-extinction of clones carrying TCRalpha-driven TLX1 expression supports TLX 'addiction' in TLX-positive leukemias and provides further rationale for targeted therapy based on disruption of TLX1/TLX3.

2012-07-17 | E-MEXP-3527 | biostudies-arrayexpress

Expression data from mouse T-cell lymphomas

Project description:Transgenic expression of key transcritpion factors inducing T-cell leukemias in mice. We used microarrays to identify the gene expression signatures associated with TLX1transgenic /RUNX1 heterozygous tumors compared with different genetic models T acute lymphoblastic lymphoma. RNA extraction from T-cell tumors from mice with different T-cell lymphoma-predisposing genetic backgrounds.

2011-11-08 | E-GEOD-33549 | biostudies-arrayexpress

KDM4A regulated gene expression in human prostate cancer LNCaP cell

Project description:Histone lysine demethylase KDM4A is overexpressed in prostate cancer and plays a crucial role in tumor growth and survival. To understand the mechanisms underlying KDM4A-depedent cell growth and survival, microarray analysis was performed in LNCaP cells transduced with control or KDM4A specific-knockdown construct. The role of KDM4A in prostate carcinogenesis involves activation of E2F1 and androgen receptor transcriptional profiles. LNCaP cells were transduced by lentivirus carrying control pLKO.1 (empty vector) or shKDM4A construct (KDM4A-specific shRNA) for three days, followed by RNA extraction. Affymetrix GeneChip Human Genome U133 Plus 2.0 Arrays were used for microarray analysis.

2016-07-26 | E-GEOD-77928 | biostudies-arrayexpress

The homeobox transcription factor Nkx2-1 regulates microRNAs controlling downstream gene silencing in lung epithelial cells (microRNA)

Project description:Cell-specific gene expression is achieved by a combination of mechanisms including transcriptional and post-transcriptional regulation. The transcription factor Nkx2-1, essential for lung cell differentiation, mainly acts in transcriptional activation but can directly or indirectly repress gene expression. microRNAs are a class of small non-coding RNA that control one of the major mechanisms of gene repression. To identify miRNAs regulated by Nkx2-1 that may mediate its repressing effects, we knocked-down Nkx2-1 in mouse lung epithelial cell lines and systematically identified targets by genome-wide miR and mRNA expression analyses. Nkx2-1 controls expression of miRs known to contribute to lung cell differentiation in development and disease and others not previously described. Amongst the significantly altered miRs, the mir-106a-363 cluster, miR-1195, miR-378, and miR-346 are directly correlated with the levels of Nkx2-1, whereas miR-200c/b, miR-221, and miR- 222 are inversely correlated. These miRNAs are expressed in embryonic lung at day E11.5, and/or E19.5 determined by in-situ hybridization. Expression of predicted targets of mir-1195, mir-346 and miR-200c and mir-221/222 were evaluated by mRNA expression microarrays in Nkx2-1 knockdown cells identifying those anti-correlated to the corresponding miRNA expression. Genes regulated by mir-1195, Cyp2s1 and Map3k2, by mir-346, Klf6, and miR-200c, Myb, Nfib, and Six1, were validated by qRT-PCR. Inhibition of mir-1195 confirms the inverse correlation of this miRNA with its putative targets Cyp2s1 and Map3k2. This miRNA-mRNA expression analysis identifies potential paths of Nkx2-1 mediated gene repression, and contributes to the understanding of gene regulation in lung epithelial differentiation and development. Nkx2-1 mRNA was knocked down in lung epithelial cells using a lentivirus expressing a shRNA targeting Nkx2-1 (n=3) and compared to empty vector controls (n=3).

2015-12-22 | E-GEOD-47053 | biostudies-arrayexpress

The homeobox transcription factor Nkx2-1 regulates microRNAs controlling downstream gene silencing in lung epithelial cells (mRNA)

2015-12-22 | E-GEOD-47054 | biostudies-arrayexpress

Gene regulation in hematopoietic cells by Pcgf1 in a Runx1 null background

Project description:The transcription factor Runx1 is essential for the establishment of definitive hematopoiesis during embryonic development. In adult blood homeostasis, Runx1 plays a pivotal role in the maturation of lymphocytes and megakaryocytes. Furthermore, Runx1 is required for the regulation of hematopoietic stem and progenitor cell (HSPC) pools. However, how Runx1 orchestrates self-renewal and lineage choices in combination with other factors is not well understood. Here we describe a genome-scale RNAi screen to detect genes that cooperate with Runx1 in regulating HSPCs. We identify the polycomb group protein Pcgf1 as an epigenetic regulator involved in hematopoietic cell differentiation. We show that simultaneous depletion of Runx1 and Pcgf1 allows sustained self-renewal while blocking differentiation of HSPCs in vitro. We find an upregulation of HoxA cluster genes upon Pcgf1 knockdown that possibly accounts for the increase in self-renewal. Further, our data suggest that cells lacking both Runx1 and Pcgf1 are blocked at an early progenitor stage, indicating that a concerted action of the transcription factor Runx1 together with the epigenetic repressor Pcgf1 is necessary for terminal differentiation. Thus, our work discovers a genetic link between transcriptional and epigenetic regulation that is required for hematopoietic differentiation. Hematopoietic stem and precursor cells freshly isolated from mice were transduced with an shRNA targeting Pcgf1 or a control shRNA. Cells were selected with puromycin for 36 h before total mRNA was isolated.

2012-06-17 | E-GEOD-33280 | biostudies-arrayexpress

Cooperation between TLX1 and the NUP214-ABL1/STAT5 signaling in T-cell acute lymphoblastic leukemia

Project description:The NUP214-ABL1 fusion is a constitutively activated tyrosine kinase that is significantly associated with overexpression of the TLX1 or TLX3 transcription factors in T-cell acute lymphoblastic (T-ALL). Here we show that NUP214-ABL1 kinase cooperates with TLX1 in driving T-ALL development using a transgenic mouse model. Using ChIP-seq and ATAC-seq, we show that TLX1 and STAT5, the downstream effector of NUP214-ABL1, selectively increase the accessibility of enhancer regions, and cooperatively activate the expression of key proto-oncogenes such as MYC and BCL2. Moreover, MYC is also part of the TLX1/STAT5 complex and inhibition of both MYC and STAT5 leads to reduction of target gene expression.

2018-06-26 | GSE102209 | GEO

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