The co-receptor Neuropilin-1 enhances proliferation in inv(16) acute myeloid leukemia via VEGF signaling
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE215613 | GEO | 2024/11/18
REPOSITORIES: GEO
Similar Datasets
Project description:Different mechanisms for CBF-MYH11 function in acute myeloid Leukemia (AML) with inv(16) have been proposed such as tethering of RUNX1 outside the nucleus, interference with transcription factor complex assembly and recruitment of histone deacetylases, all resulting in transcriptional repression of RUNX1 target genes. Here, through genome-wide CBF-MYH11 binding site analysis and quantitative interaction proteomics we found that CBF-MYH11 localizes to RUNX1 occupied promoters where it interacts with TAL1, FLI1 and TBP associated factors (TAFs) in the context of the hematopoietic transcription factors ERG, GATA2 and PU.1/SPI1 and the co regulators EP300 and HDAC1. Transcriptional analysis revealed that upon fusion protein knock down a subset of the CBF-MYH11 target genes show increased expression, confirming a role in transcriptional repression. However, the majority of CBF-MYH11 target genes, including genes implicated in hematopoietic stem cell (HSC) self-renewal such as ID1, LMO1 and JAG1, are actively transcribed and upon fusion protein knock down repressed. Together these results suggest an essential role for CBF-MYH11 in regulating expression of genes involved in maintaining a stem cell phenotype.
2013-09-09 | GSE46044 | GEO
Project description:Different mechanisms for CBF-MYH11 function in acute myeloid Leukemia (AML) with inv(16) have been proposed such as tethering of RUNX1 outside the nucleus, interference with transcription factor complex assembly and recruitment of histone deacetylases, all resulting in transcriptional repression of RUNX1 target genes. Here, through genome-wide CBF-MYH11 binding site analysis and quantitative interaction proteomics we found that CBF-MYH11 localizes to RUNX1 occupied promoters where it interacts with TAL1, FLI1 and TBP associated factors (TAFs) in the context of the hematopoietic transcription factors ERG, GATA2 and PU.1/SPI1 and the co regulators EP300 and HDAC1. Transcriptional analysis revealed that upon fusion protein knock down a subset of the CBF-MYH11 target genes show increased expression, confirming a role in transcriptional repression. However, the majority of CBF-MYH11 target genes, including genes implicated in hematopoietic stem cell (HSC) self-renewal such as ID1, LMO1 and JAG1, are actively transcribed and upon fusion protein knock down repressed. Together these results suggest an essential role for CBF-MYH11 in regulating expression of genes involved in maintaining a stem cell phenotype. 17 ChIP-seq samples using antibodies recognizing the indicated proteins and one RNA-seq file from ME-1 cells were analyzed. In addition 2 ChIP-seq profiles were generated using patient AML cells. A CBFβ-MYH11 inducible U937 system (U937CM) was used to examine binding patterns before (1 profile) and after (2 profiles) induction of CBFb-MYH11. In addition, expression was measured through RNA-seq analysis of the two states. The U937CM cells were maintained in the presence of tetracyclin (Tet, 1 uM) and grown in the absence of tetracycline for 3 days to induce expression of CBFβ-MYH11. Finally, a CBFb-MYH11 knock down system was developed in ME-1 cells. Two ME-1 cell lines were created, one with a stably integrated shRNA construct that targets CBFb-MYH11 (ME-1_knockdown) and one with a scrambled shRNA construct (ME-1_SCR). Expression of the shRNA constructs was induced using doxycyclin (dox; 1 mM) treatment for 3 days.
2013-09-09 | E-GEOD-46044 | biostudies-arrayexpress
Project description:The CBFβ-MYH11 fusion generated by inv(16) aberration is proposed to block normal myeloid differentiation, but whether this subtype of leukemia cells is poised for an unique cell lineage remains unclear. Here, we surveyed the functional consequences of CBFβ-MYH11 in inv(16) patient blasts and two inducible systems by multi-omics profiling. The primary inv(16) cells stay closer with megakaryocyte and erythrocyte lineages along the cell differentiation trajectory, and share common transcriptomic signatures and epigenetic determiners. Using in vitro differentiation systems, we reveal that CBFβ-MYH11 knockdown establishes normal endomitosis-related processes, which are crucial for megakaryocyte maturation. Two pivotal regulators, GATA2 and KLF1, are identified to complementally occupy RUNX1 binding sites upon the fusion protein knockdown. Overexpression of GATA2 partly restores megakaryocyte directed differentiation suppressed by CBFβ-MYH11, and additional factors like KLF1 and EGR1 might be required to coordinately prevent CFB-MYH11 leukemogenesis. Together, our findings suggest that in inv(16) leukemia, the CBFβ-MYH11 fusion inhibits primed megakaryopoiesis by interfering with a balanced transcriptional program involving GATA2 and KLF1.
2019-03-22 | GSE117138 | GEO
Project description:<p>Pediatric <i>de novo</i> acute myeloid leukemia (AML) is a heterogeneous disease that can be divided into clinically distinct subtypes based on the presence of specific chromosomal abnormalities or gene alterations. One of the best characterized subtypes of AML involves leukemias with alterations of the core-binding factor (CBF)-complex, which comprises the FAB subtypes M2 and M4Eo and associates with a favorable outcome. Patients with the AML M2 subtype harbor a translocation between chromosomes 8 and 21 [t(8;21)] that yields the chimeric fusion gene <i>RUNX1(AML1)-RUNX1T1(ETO)</i>, while patients with AML M4Eo express the chimeric fusion gene <i>CBFβ-SMMHC(MYH11)</i> as a result of an inversion/translocation event of chromosome 16 [inv(16)/t(16;16)]. In an effort to define the total complement of genetic changes in CBF-leukemia, we performed paired-end whole genome sequencing (WGS) on diagnostic leukemia blasts and matched germ line samples from 17 pediatric CBF-leukemia patients using the Illumina platform. Somatic alterations, including single nucleotide variations (SNVs) and structural variations (SVs), including insertions, deletions, inversions, and inter- and intra-chromosomal rearrangements, were detected using complementary analysis pipelines (Bambino, CREST and CONSERTING). Recurrent screening of identified mutations will be performed in a cohort of approximately 94 cases of CBF-leukemias.</p>
| phs000414 | dbGaP
Project description:Core binding factor (CBF) leukemias, characterized by either inv(16)/t(16;16) or t(8;21), constitute acute myeloid leukemia (AML) subgroups with favorable prognosis. However, there exists substantial biological and clinical heterogeneity within these cytogenetic groups, which is not fully reflected by the current classification system. To improve the molecular characterization we profiled gene expression in a large series (n=93) of AML patients with CBF leukemia [inv(16) n=55, t(8;21) n=38]. By unsupervised hierarchical clustering we were able to define a subgroup of CBF cases (n=35) characterized by shorter overall survival times (P=0.03). While there was no obvious correlation with fusion gene transcript levels, FLT3 tyrosine kinase domain, KIT, and NRAS mutations, the newly defined inv(16)/t(8;21)-subgroup was associated with elevated white blood cell counts and FLT3 internal tandem duplications (P=0.011 and P=0.026, respectively). Supervised analyses of gene expression suggested alternative cooperating pathways leading to transformation. In the ?favorable? CBF leukemias anti-apoptotic mechanisms and deregulated mTOR-signaling, and in the newly defined ?unfavorable? subgroup aberrant MAPKinase-signaling and chemotherapy-resistance mechanisms might play a role. While the leukemogenic relevance of these signatures remains to be validated, their existence nevertheless supports a prognostically relevant biological basis for the heterogeneity observed in CBF leukemia.
2007-06-10 | E-SMDB-4056 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) harboring inv(16)(p13q22) expresses high levels of miR-126. Here we show that the CBFB-MYH11 (CM) fusion gene upregulates miR-126 expression through aberrant miR-126 transcription and perturbed miR-126 biogenesis via the HDAC8/RAN-XPO5-RCC1 axis. Aberrant miR-126 upregulation promotes survival of leukemia-initiating progenitors and is critical for initiating and maintaining CM-driven AML. We show that miR-126 enhances MYC activity through the SPRED1/PLK2-ERK-MYC axis. Notably, genetic deletion of miR-126 significantly reduced AML rate and extended survival in CM knock-in mice. Therapeutic depletion of miR-126 with an anti-miR-126 (miRisten) inhibited AML cell survival, reduced leukemia burden and leukemia stem cell (LSC) activity in inv(16) AML murine and xenograft models. Combination of miRisten with chemotherapy further enhanced the anti-leukemia and anti-LSC activity. Overall, this study provides molecular insights for the mechanism and impact of miR-126 dysregulation in leukemogenesis and highlights the potential of miR-126 depletion as a new therapeutic approach for inv(16) AML.
2021-09-15 | GSE184015 | GEO
Project description:Core binding factor (CBF) leukemias, characterized by either inv(16)/t(16;16) or t(8;21), constitute acute myeloid leukemia (AML) subgroups with favorable prognosis. However, there exists substantial biological and clinical heterogeneity within these cytogenetic groups, which is not fully reflected by the current classification system. To improve the molecular characterization we profiled gene expression in a large series (n=93) of AML patients with CBF leukemia [inv(16) n=55, t(8;21) n=38]. By unsupervised hierarchical clustering we were able to define a subgroup of CBF cases (n=35) characterized by shorter overall survival times (P=0.03). While there was no obvious correlation with fusion gene transcript levels, FLT3 tyrosine kinase domain, KIT, and NRAS mutations, the newly defined inv(16)/t(8;21)-subgroup was associated with elevated white blood cell counts and FLT3 internal tandem duplications (P=0.011 and P=0.026, respectively). Supervised analyses of gene expression suggested alternative cooperating pathways leading to transformation. In the ?favorable? CBF leukemias anti-apoptotic mechanisms and deregulated mTOR-signaling, and in the newly defined ?unfavorable? subgroup aberrant MAPKinase-signaling and chemotherapy-resistance mechanisms might play a role. While the leukemogenic relevance of these signatures remains to be validated, their existence nevertheless supports a prognostically relevant biological basis for the heterogeneity observed in CBF leukemia. A reference experiement design type is where all samples are compared to a common reference. Keywords: reference_design
2007-08-09 | GSE8653 | GEO
Project description:Core binding factor (CBF) leukemias, characterized by either inv(16)/t(16;16) or t(8;21), constitute acute myeloid leukemia (AML) subgroups with favorable prognosis. However, there exists substantial biological and clinical heterogeneity within these cytogenetic groups, which is not fully reflected by the current classification system. To improve the molecular characterization we profiled gene expression in a large series (n=93) of AML patients with CBF leukemia [inv(16) n=55, t(8;21) n=38]. By unsupervised hierarchical clustering we were able to define a subgroup of CBF cases (n=35) characterized by shorter overall survival times (P=0.03). While there was no obvious correlation with fusion gene transcript levels, FLT3 tyrosine kinase domain, KIT, and NRAS mutations, the newly defined inv(16)/t(8;21)-subgroup was associated with elevated white blood cell counts and FLT3 internal tandem duplications (P=0.011 and P=0.026, respectively). Supervised analyses of gene expression suggested alternative cooperating pathways leading to transformation. In the ?favorable? CBF leukemias anti-apoptotic mechanisms and deregulated mTOR-signaling, and in the newly defined ?unfavorable? subgroup aberrant MAPKinase-signaling and chemotherapy-resistance mechanisms might play a role. While the leukemogenic relevance of these signatures remains to be validated, their existence nevertheless supports a prognostically relevant biological basis for the heterogeneity observed in CBF leukemia. A reference experiement design type is where all samples are compared to a common reference. Using regression correlation
2007-08-09 | E-GEOD-8653 | biostudies-arrayexpress
Project description:The hematopoietic system is maintained throughout life by hematopoietic stem cells that are capable of differentiation to all hematopoietic lineages. An intimate balance between self-renewal, differentiation, and quiescence is required to maintain hematopoiesis. Disruption of this balance can result in hematopoietic malignancy, including acute myeloid leukemia (AML). FBXO9, from the F-box ubiquitin E3 ligases, is down-regulated in patients with AML compared to normal bone marrow. FBXO9 is a substrate recognition component of the Skp1-Cullin-F-box (SCF)-type E3 ligase complex. FBXO9 is highly expressed in hematopoietic stem and progenitor populations, which contain the tumor-initiating population in AML. In AML patients, decrease in FBXO9 expression is most pronounced in patients with the inversion of chromosome 16 (Inv(16)), a rearrangement that generates the transcription factor fusion gene, CBFB-MYH11. To study FBXO9 in malignant hematopoiesis, we generated a conditional knockout mouse model using a novel CRISPR/Cas9 strategy. Our data shows that deletion of Fbxo9 in mice expressing Cbfb-MYH11 leads to markedly accelerated and aggressive leukemia development. In addition, we find loss of FBXO9 leads to increased proteasome expression and tumors are more sensitive to bortezomib suggesting that FBXO9 expression may predict patient response to bortezomib treatment.
2019-11-27 | PXD014387 | Pride
Project description:The transcription factor (TF) GATA2, is crucial for the formation, and lifelong homeostasis of hematopoietic stem cells. Mono-Allelic germline disruptions of GATA2, result in haploinsufficiency syndromes. These disorders display variable manifestations, including immune deficiency, lymphedema, pulmonary proteinosis, and bone marrow failure. The later is presented by myelodysplastic changes (MDS), that subsequently evolve to leukemia (AML). MDS/AML are the most devastating, yet most consistent outcomes, designating GATA2 deficiency as one major predisposing condition to AML development. To date, biomolecular trajectories of GATA2 deficiency, just vaguely delineated explanatory mechanisms. Experimental models recapitulating the disease evolution are meager, and functional studies are thus hampered. Here, we created murine models, reflecting the evolution of GATA2 deficiency, from gestational stage, to malignancy. We imposed the oncogenic driving force of TF ERG, upon Gata2 heterozygote and WT mice, to create a credible model. Both ERG/Gata2WT, and ERG/Gata2het mice developed leukemia, yet ERG/Gata2het, sustained an accelerated disease, resulting in diminished survival (p<0.0001). Subsequently, we obtained expression profiles of pre-leukemic blood precursors, using high throughput genomics, followed by functional assessments of self-renewal and cycling capacities. These studies elucidated a unique proliferative phenotype held by ERG/Gata2het progenitors. Additional expression analyses, metabolic assays, and electrons-microscopy inspections, suggested ERG/Gata2het progenitors uniquely relay on oxidative phosphorylation, and harbor alterations in mitochondrial structure and function. Excitingly, similar expression signature and morphological features were observed in human GATA2+/R396W cells, and in profiles of Inv(3)/GATA2MUT AML’s. We here provide new insights into GATA2 deficiency evolutionary course, underscoring the need to deconvolute pre-malignant stages in translational studies.
2022-07-01 | GSE143238 | GEO