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Single cell characterization of arrested B-lymphoid differentiation and leukemic cell states in ETV6-RUNX1-positive pediatric leukemia

ABSTRACT: Arrested bone marrow (BM) lymphoid cell differentiation underlies the emergence of the most common childhood cancer, acute lymphoblastic leukemia (ALL). Recurrent genetic lesions often directly involve transcription factors (TFs), such as ETV6 and RUNX1 found in the most common ALL translocation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148189 | GEO | 2020/10/30

REPOSITORIES: GEO

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Single cell characterization of arrested B-lymphoid differentiation and leukemic cell states in ETV6-RUNX1-positive pediatric leukemia

Project description:Arrested bone marrow (BM) lymphoid cell differentiation underlies the emergence of the most common childhood cancer, acute lymphoblastic leukemia (ALL). Recurrent genetic lesions often directly involve transcription factors (TFs), such as ETV6 and RUNX1 found in the most common ALL translocation. Here, we studied differential gene expression in ETV6-RUNX1 primary ALL samples and the REH cell line using single cell RNA-seq (scRNA-seq). Submitter declares that the raw data will be deposited in EGA due to patient privacy concerns. The raw data can be accessed at https://www.ebi.ac.uk/ega/studies/EGAS00001004374

2020-10-30 | GSE148218 | GEO

Single cell characterization of arrested B-lymphoid differentiation and leukemic cell states in ETV6-RUNX1-positive pediatric leukemia

Project description:Single cell characterization of arrested B-lymphoid differentiation and leukemic cell states in ETV6-RUNX1-positive pediatric leukemia

| PRJNA623408 | ENA

Single cell characterization of arrested B-lymphoid differentiation and leukemic cell states in ETV6-RUNX1-positive pediatric leukemia

Project description:Single cell characterization of arrested B-lymphoid differentiation and leukemic cell states in ETV6-RUNX1-positive pediatric leukemia

| PRJNA623525 | ENA

Single cell characterization of arrested B-lymphoid differentiation and leukemic cell states in ETV6-RUNX1-positive pediatric leukemia

Project description:Genetic hits in the gene regulatory network underlie arrested lymphoid cell differentiation and emergence of the most common childhood cancer, acute lymphoblastic leukemia (ALL). Here, we aimed to understand what alterations in the lymphoid gene expression program arise in leukemias carrying the common translocation t12;21, fusing the ETV6 and RUNX1 genes. We compared normal B-lineage differentiation and in vivo leukemic cell states at diagnosis and during chemotherapy using single cell RNA-sequencing (scRNA-seq) and several complementary genomics assays. We show that noisy gene expression of critical pre-BCR signaling pathway genes arises as a consequence of ETV6-RUNX1-mediated repression of intronic enhancers. Furthermore, our analysis implicated the genome-wide association study hit ELK3 among high activity transcription factors in leukemic cell states. The accompanying gene expression changes were found to associate with natural killer cell inactivation and depletion in the leukemic immune microenvironment. Moreover, our results suggest that the abundance of G1 cell cycle state at diagnosis and lack of differentiation-associated regulatory network changes represent features of chemoresistance during induction chemotherapy. Finally, we show that selective inhibitors of ETS-transcription factors could dramatically reduce cell viability. In summary, our results provide a detailed picture of gene regulatory defects in leukemic bone marrow, disclosing mechanistic insight on the role of gene expression noise and suggesting new treatment strategies targeting the active regulatory network.

| EGAS00001004374 | EGA

Loss of BTG1 function promotes ETV6-RUNX1-mediated leukemic transformation by upregulation of BCL6

Project description:Analysis of gene signatures in WT+Ctrl vs WT+ETV6-RUNX1, Btg1-/- and Btg1-/-+ETV6-RUNX1 in cKit+Ter119- fetal liver-derived hematopoietic progenitor cells (FL-HPCs). The Btg1-/-+ETV6-RUNX1 FL-HPCs display a strong increase in proliferation compared to WT+ETV6-RUNX1. Total RNA otained from WT+Ctrl, WT+ETV6-RUNX1, Btg1-/-+Ctrl and Btg1-/-+ETV6-RUNX1 FL-HPCs cells that were cultured for 12 days in expansion medium.

2014-08-22 | E-GEOD-60589 | biostudies-arrayexpress

Loss of BTG1 function promotes ETV6-RUNX1-mediated leukemic transformation by upregulation of BCL6

2014-08-22 | GSE60589 | GEO

ChIP-seq for RUNX1 and ETV6-RUNX1 in an induced pluripotent stem cell model of ETV6-RUNX1 pre-leukaemia

Project description:ETV6-RUNX1 is a first-hit mutation in childhood B cell precursor acute lymphoblastic leukaemia. ETV6-RUNX1 is a fusion protein which inherits the DNA-binding runt domain from RUNX1. Here we performed chromatin precipitation for native RUNX1 and ETV6-RUNX1 using RUNX1 antibodies and specifically for the ETV6-RUNX1 fusion using a V5-tag pull down.

2022-10-31 | E-MTAB-12208 | biostudies-arrayexpress

Genome wide mapping of ETV6 binding sites in pre-B leukemic cells

Project description:Background: Genetic alterations in the transcriptional repressor ETV6 are associated with hematological malignancies. Notably, the t(12;21) translocation leading to an ETV6-AML1 fusion gene is the most common genetic alteration found in childhood acute lymphoblastic leukemia. Moreover, most of these patients also lack ETV6 expression, suggesting a tumor suppressor function. Results: To gain insights on ETV6 DNA-binding specificity and genome wide transcriptional regulation capacities, we performed chromatin immunoprecipitation experiments coupled to deep sequencing in a t(12;21)-positive pre-B leukemic cell line. This strategy led to high quality ETV6-bound regions. ETV6 binding is mostly cell type-specific as only few regions are shared with other blood cell subtypes. Peaks localization and motif enrichment analyses revealed a unique binding profile that is associated with the presence of the ETV6-AML1 fusion product. Conclusions: We described the first ETV6 binding map in the t(12;21) background. This study highlighted the complex and unique interplay between ETV6 and ETV6-AML1 and underscored the highly regulated mechanisms of ETV6 binding. ETV6 inactivation observed in this context could induce specific transcriptional changes promoting leukemic transformation.

2017-11-15 | GSE102785 | GEO

Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1-positive pediatric leukemia identifies drug-targetable transcription factor activities.

Project description: Not available

| S-EPMC7679990 | biostudies-literature

Identification of ETV6 bound protein by affinity purification of ETV6-HA fusion protein in REH cells

Project description:To determine the protein partners of ETV6, we expressed ETV6 and HA-tagged ETV6 in Reh pre-B leukemic cells. Anti-HA magnetic beads were used for affinity purification of ETV6-HA (and ETV6 control) from the nuclear and cytoplasmic fraction. Following purification on-beads digest and LC-MS/MS experiments were performed at the Proteomics platform of the CHU de Quebec Research Center, Quebec, Canada.

2022-01-26 | PXD031001 | Pride

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