GATA2 regulates the erythropoietin receptor in t(12;21) ALL

Gaine, Marie E.; Sharpe, Daniel; Smith, J. S.; Colyer, Hilary A. A.; Hodges, Vivien M.; Lappin, Terry R.J.; Mills, Ken

doi:10.18632/oncotarget.19792

Cited by 8 publications

(7 citation statements)

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“…On the other hand, we showed that GATA2 was actively transcribed in a subset of B-ALL patients, especially in those with the ETV subtype (Figure 1B). The transcription of GATA2 in ETV-subtype B-ALL patients is supported by a recent study carried out with the B-ALL cell lines REH and Nalm6, which belong to the ETV and DUX4 subtypes respectively, suggesting potential association between GATA2 transcription and gene methylation (42). In addition, we discovered 13 B-ALL cases with aberrant GATA2 activation from 629 B-ALL patients, indicating that GATA2 dysregulation is a shared feature of different B-ALL subtypes.…”

Section: Discussionsupporting

confidence: 77%

Aberrant GATA2 Activation in Pediatric B-Cell Acute Lymphoblastic Leukemia

et al. 2022

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GATA2 is a transcription factor that is critical for the generation and survival of hematopoietic stem cells (HSCs). It also plays an important role in the regulation of myeloid differentiation. Accordingly, GATA2 expression is restricted to HSCs and hematopoietic progenitors as well as early erythroid cells and megakaryocytic cells. Here we identified aberrant GATA2 expression in B-cell acute lymphoblastic leukemia (B-ALL) by analyzing transcriptome sequencing data obtained from St. Jude Cloud. Differentially expressed genes upon GATA2 activation showed significantly myeloid-like transcription signature. Further analysis identified several tumor-associated genes as targets of GATA2 activation including BAG3 and EPOR. In addition, the correlation between KMT2A-USP2 fusion and GATA2 activation not only indicates a potential trans-activating mechanism of GATA2 but also suggests that GATA2 is a target of KMT2A-USP2. Furthermore, by integrating whole-genome and transcriptome sequencing data, we showed that GATA2 is also cis activated. A somatic focal deletion located in the GATA2 neighborhood that disrupts the boundaries of topologically associating domains was identified in one B-ALL patient with GATA2 activation. These evidences support the hypothesis that GATA2 could be involved in leukemogenesis of B-ALL and can be transcriptionally activated through multiple mechanisms. The findings of aberrant activation of GATA2 and its molecular function extend our understanding of transcriptional factor dysregulation in B-ALL.

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Section: Discussionsupporting

confidence: 77%

Aberrant GATA2 Activation in Pediatric B-Cell Acute Lymphoblastic Leukemia

et al. 2022

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“…Through computational discovery and analysis of TF regulons from scRNA-seq data, and independent validation with bulk genomics data, we could show that elevated activity of multiple ETS-factors (ELK3, ERG, and FLI1) together with pro-B TFs FOXO1, MEF2C, immature B cell TFs NFYC, RFX5, lineage-atypical GATA2 expression, and E/R subtype-specific SP4 and TCFL5 activities characterized the E/R+ regulatory network. TCFL5 has been previously shown to be upregulated in E/R+ pre-B-ALL [ 107 – 109 ], while GATA2 has been reported to contribute to the upregulation of erythroid genes, such as EPOR , a known marker gene in E/R+ leukemia [ 110 – 112 ]. While these TF activities were consistently high across the six diagnostic samples studied, many IRF- and STAT-regulons showed variable activity.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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Background Tight regulatory loops orchestrate commitment to B cell fate within bone marrow. Genetic lesions in this gene regulatory network underlie the emergence of the most common childhood cancer, acute lymphoblastic leukemia (ALL). The initial genetic hits, including the common translocation that fuses ETV6 and RUNX1 genes, lead to arrested cell differentiation. Here, we aimed to characterize transcription factor activities along the B-lineage differentiation trajectory as a reference to characterize the aberrant cell states present in leukemic bone marrow, and to identify those transcription factors that maintain cancer-specific cell states for more precise therapeutic intervention. Methods We compared normal B-lineage differentiation and in vivo leukemic cell states using single cell RNA-sequencing (scRNA-seq) and several complementary genomics profiles. Based on statistical tools for scRNA-seq, we benchmarked a workflow to resolve transcription factor activities and gene expression distribution changes in healthy bone marrow lymphoid cell states. We compared these to ALL bone marrow at diagnosis and in vivo during chemotherapy, focusing on leukemias carrying the ETV6-RUNX1 fusion. Results We show that lymphoid cell transcription factor activities uncovered from bone marrow scRNA-seq have high correspondence with independent ATAC- and ChIP-seq data. Using this comprehensive reference for regulatory factors coordinating B-lineage differentiation, our analysis of ETV6-RUNX1-positive ALL cases revealed elevated activity of multiple ETS-transcription factors in leukemic cells states, including the leukemia genome-wide association study hit ELK3. The accompanying gene expression changes associated 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 during induction chemotherapy represent features of chemoresistance. To target the leukemic regulatory program and thereby overcome treatment resistance, we show that inhibition of ETS-transcription factors reduced cell viability and resolved pathways contributing to this using scRNA-seq. Conclusions Our data provide a detailed picture of the transcription factor activities characterizing both normal B-lineage differentiation and those acquired in leukemic bone marrow and provide a rational basis for new treatment strategies targeting the immune microenvironment and the active regulatory network in leukemia.

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“…Through computational discovery and analysis of TF regulons from scRNA-seq data, and independent validation with GRO-seq and bulk genomics data, we could show that elevated activity of multiple ETS-factors (ELK3, ERG and FLI1), together with pro-B TFs FOXO1, MEF2C, immature B-cell TFs NFYC, RFX5, lineage-atypical GATA2 expression and E/R-subtype-specific SP4 and TCFL5 activities characterized the E/R+ regulatory network. TCFL5 has been previously shown to be upregulated in E/R+ pre-B-ALL [65][66][67], while GATA2 has been reported to contribute in the upregulation of erythroid genes, such as EPOR, a known marker gene in E/R+ leukemia [68][69][70]. While these TF activities were consistently high across the six diagnostic samples studied, many IRF-and STAT-regulons showed variable activity.…”

Section: Single Cell Profiling Techniques Have Challenged How We Defimentioning

confidence: 87%

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

Mehtonen

Teppo

Lahnalampi

et al. 2020

Preprint

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Tight regulatory loops orchestrate commitment to B-cell fate within bone marrow. Genetic lesions in this gene regulatory network underlie the emergence of the most common childhood cancer, acute lymphoblastic leukemia (ALL). The initial genetic hits, including the common translocation that fuses ETV6 and RUNX1 genes, lead to arrested cell differentiation. Here, we aimed to characterize transcription factor activities along the B-lineage differentiation trajectory as a reference to characterize the aberrant cell states present in leukemic bone marrow, and to identify those transcription factors that maintain cancer-specific cell states for more precise therapeutic intervention.We compared normal B-lineage differentiation and in vivo leukemic cell states using single cell RNA-sequencing (scRNA-seq) and several complementary genomics profiles. Based on statistical tools for scRNA-seq, we benchmarked a workflow to resolve transcription factor activities and gene expression distribution changes in healthy bone marrow lymphoid cell states. We compared these to ALL bone marrow at diagnosis and in vivo during chemotherapy, focusing on leukemias carrying the ETV6-RUNX1 fusion.We show that lymphoid cell transcription factor activities uncovered from bone marrow scRNA-seq have high correspondence with independent ATAC- and ChIP-seq data. Using this comprehensive reference for regulatory factors coordinating B-lineage differentiation, our analysis of ETV6-RUNX1-positive ALL cases revealed elevated activity of multiple ETS-transcription factors in leukemic cells states, including the leukemia genome-wide association study hit ELK3. The accompanying gene expression changes associated 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 during induction chemotherapy represent features of chemoresistance. To target the leukemic regulatory program and thereby overcome treatment-resistance, we show that selective inhibitors of ETS-transcription factors could effectively reduce cell viability.Our data provide a detailed picture of the transcription factor activities that characterize both normal B-lineage differentiation and those acquired in leukemic bone marrow and provide a rational basis for new treatment strategies targeting the immune microenvironment and the active regulatory network in leukemia.

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GATA2 regulates the erythropoietin receptor in t(12;21) ALL

Cited by 8 publications

References 50 publications

Aberrant GATA2 Activation in Pediatric B-Cell Acute Lymphoblastic Leukemia

Aberrant GATA2 Activation in Pediatric B-Cell Acute Lymphoblastic Leukemia

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

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

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