About

Emery Bresnick is the Gary Felsenfeld Professor of Cell and Regenerative Biology, the Lowell and Gwendolyn Smythe Endowed Professor, and the Director of the UW-Madison Blood Cancer Research Program. His research interests include cancer predisposition mechanisms, epigenetics, hematology, genomics, and stem/progenitor cell biology. His work focuses on understanding the epigenetic and genomic factors involved in blood cancer development and stem cell regulation, contributing to the advancement of precision medicine and regenerative biology.

Research topics

• Genetics
• Biology
• Immunology
• Medicine
• Pathology
• Cancer research
• Cell biology

Selected publications

• GATA2 links stemness to chemotherapy resistance in acute myeloid leukemia

  Blood · 2025-01-22 · 12 citations

  articleOpen access

  ABSTRACT: Stemness-associated cell states are linked to chemotherapy resistance in acute myeloid leukemia (AML). We uncovered a direct mechanistic link between expression of the stem cell transcription factor GATA2 and drug resistance. The GATA-binding protein 2 (GATA2) plays a central role in blood stem cell generation and maintenance. We find substantial intrapatient and interpatient variability in GATA2 expression across samples from patients with AML. GATA2 expression varies by molecular subtype and has been linked to outcome. In a murine model, KMT2A-MLL3-driven AML originating from a stem cell or immature progenitor cell population has higher Gata2 expression and is more resistant to the standard AML chemotherapy agent doxorubicin. Deletion of Gata2 resulted in a more robust induction of p53 after exposure to doxorubicin. Chromatin immunoprecipitation sequencing, RNA sequencing, and functional studies revealed that GATA2 regulates the expression of RASSF4, a modulator of the p53 inhibitor MDM2 (mouse double minute 2). GATA2 and RASSF4 are anticorrelated in human cell lines and in bulk and single-cell expression data sets from patients with AML. Knockdown of Rassf4 in Gata2-low cells resulted in doxorubicin or nutlin-3 resistance. Conversely, overexpression of Rassf4 results in sensitization of cells expressing high levels of Gata2. Finally, doxorubicin and nutlin-3 are synergistic in Gata2-high murine AML and in samples from patients with AML. We discovered a previously unappreciated role for GATA2 in dampening p53-mediated apoptosis via transcriptional regulation of RASSF4, a modulator of MDM2. This role for GATA2 directly links the expression of a stemness-associated transcription factor to chemotherapy resistance.

  PublisherOA PDFDOI

• Loss of GATA2 promotes invasion and predicts cancer recurrence and survival in uterine serous carcinoma

  JCI Insight · 2025-04-01

  articleOpen access

  BACKGROUNDA priori knowledge of recurrence risk in patients with nonmetastatic (International Federation of Gynecology and Obstetrics [FIGO] stage I) uterine serous carcinoma (USC) would enable a risk-stratified approach to the use of adjuvant chemotherapy. This would greatly reduce treatment-related morbidity and be predicted to improve survival.METHODSGATA2 expression was scored by IHC across a retrospective multiinstitutional cohort of 195 primary USCs. Associations between GATA2 levels and clinicopathologic metrics were evaluated using Student's t test, Fisher's exact test, Kaplan-Meier method, and Cox proportional hazard ratio. Invasion in patient-derived USC cells was assessed by Student's t test. RNA-Seq, anti-GATA2 ChIP-Seq, and confirmatory Western blotting enabled identification of GATA2 targets.RESULTSPatients with FIGO stage I GATA2hi USCs had 100% recurrence-free and 100% cancer-related survival, which was significantly better than patients with GATA2lo USCs. In patients for whom adjuvant chemotherapy was omitted, patients with GATA2hi USC had 100% recurrence-free 5-year survival compared with 60% recurrence-free survival in patients with GATA2lo USC. Depletion of GATA2 in patient-derived USC cells increased invasion in vitro.CONCLUSIONRoutine GATA2 IHC identifies 33% of patients with FIGO stage I USC who have a greatly reduced risk of posthysterectomy USC recurrence. Our results suggest that a GATA2-guided personalized medicine approach could be rapidly implemented in most hospital settings, would reduce treatment-related morbidity, and would likely improve outcomes in patients with USC.FUNDINGNIH grants R01 DK068634, P30 CA014520, S10 OD023526, K08 DK127244, T32 HL007899, the UW-Madison Department of Pathology and Laboratory Medicine, the UW-Madison Centennial Scholars Program, the Diane Lindstrom Foundation, the American Cancer Society, the V Foundation, The Hartwell Foundation, and the UMN Department of Obstetrics, Gynecology, and Women's Health.

  PublisherOA PDFDOI

• Dual mechanism of inflammation sensing by the hematopoietic progenitor genome

  Science Advances · 2025-05-28 · 3 citations

  articleOpen accessSenior authorCorresponding

  Genomes adapt dynamically to alterations in the signaling milieu, including inflammation that transiently or permanently disrupts genome function. Here, we elucidate how a progenitor cell genome senses and responds to inflammation when the developmental and transcriptional regulator GATA2 is limiting, which causes bone marrow failure in humans and mice and predisposes to leukemia in humans. GATA2 low murine progenitors are hypersensitive to inflammatory mediators. We discovered that the hematopoietic transcription factor PU.1 conferred transcriptional activation in GATA2 low progenitors in response to Interferon-γ and Toll-Like Receptor 1/2 agonists. In a locus-specific manner, inflammation reconfigured genome activity by promoting PU.1 recruitment to chromatin or tuning activity of PU.1-preoccupied chromatin. The recruitment mechanism disproportionately required IKKβ activity. Inflammation-activated genes were enriched in motifs for RUNX factors that cooperate with GATA factors. Contrasting with the GATA2-RUNX1 cooperativity paradigm, GATA2 suppressed and RUNX1 promoted PU.1 mechanisms to endow the progenitor genome with inflammation-sensing capacity.

  PublisherDOI

• Oncogenic DEAD-box ATPase DDX41 establishes transcript ensembles via CLK3-dependent and -independent mechanisms

  Nature Communications · 2025-11-05 · 1 citations

  articleOpen accessSenior author

  Post-transcriptional diversification of RNA transcripts mediated by complex processing machinery, including DEAD-box ATPases, establishes and maintains cellular phenotypes. For example, DDX41 controls RNA splicing, innate immune signaling, and genome stability. Although heterozygous DDX41 germline genetic variation occurs in familial myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), the DDX41 contributions to splicing globally, biological processes, and pathogenic mechanisms are incompletely defined. Using a genetic rescue system with Ddx41+/− myeloid progenitors, we established global wildtype DDX41 and pathogenic variant mechanisms. Differing from pathogenic variants of other RNA splicing regulators, DDX41 deficiency compromised multiple splicing steps. DDX41-regulated transcripts encoded factors controlling RNA splicing, including Cdc2-like kinase 3 (CLK3). DDX41 regulated Clk3 transcripts, and elevated CLK3 during myeloid differentiation. Loss-of-function analysis revealed DDX41-regulated splicing commonly, but not always, required CLK3. Thus, through a mechanism utilizing a splicing factor kinase that itself is DDX41-regulated, DDX41 establishes transcript ensembles in myeloid progenitors. Although DDX41 genetic variation occurs in myelodysplastic syndrome and acute myeloid leukemia, the pathogenic mechanisms remained unclear. Here, the authors found DDX41 regulates CLK3-dependent alternative splicing to establish transcript ensembles, while pathogenic variants limit the activity.

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• Building a Clinical Genetic <i>GATA2</i> Variant Curation System with Activity Metrics

  Blood · 2024-11-05

  articleSenior author

  Human GATA2 genetic variation causes GATA2 deficiency syndrome, which can lead to myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). While pathogenic GATA2 variants alter the important zinc fingers and inter-zinc finger spacer, cellular aberrations underlying the disease predisposition are not established (Bresnick et al., 2020). Furthermore, as many questions exist regarding how GATA2 controls genome function, ascribing the functional significance of variants can be challenging. Our analysis of GATA2 variants in the United States population through the All of Us Research Program database (All of Us Research Program Genomics Investigators, 2024) revealed rare zinc finger variants, e.g., C295S, R308W, T356N (1/490,000+ alleles), that had not been described. Common variants included A164T (91,211/490,000+) and P250A (962/490,000+) in the N-terminus. To advance genetic curation, we established mouse and human genetic rescue systems to generate functional signatures that discriminate GATA2 from pathogenic variants. GATA2 regulates its expression through two enhancers (-77 kb and +9.5 kb) required for hematopoietic development and function (Johnson et al., 2012; 2015). We are identifying essential GATA2-regulated enhancers genome-wide and described the importance of the GATA2-activated Cebpe +6 kb enhancer (Katsumura et al., 2024). Deletion of this enhancer in progenitors downregulated C/EBPε, expression of a GATA2-regulated gene cohort, and, surprisingly, genes regulated by the pathogenic variant T354M, which exhibits loss-of-function and gain-of-function activities. This analysis identified C/EBPε as a cooperating transcription factor with GATA2 and T354M, and Cebpe regulation did not discriminate GATA2 from T354M activity. Using multiomics with the genetic rescue system in murine Gata2 -77-enhancer-deleted myeloid progenitors (hi-77-/-) with ~75% lower GATA2, we identified metrics that discriminate GATA2 from a pathogenic variant. We compared how GATA2 and a human germline GATA2 pathogenic variant (9 amino acid insertion between the zinc fingers, 9aa-Ins) function genome-wide (Jung et al., 2023). GATA2 deficiency in hi-77-/- cells upregulated expression of innate immune genes, including Il6st and Il6ra encoding cytokine receptor subunits IL6ST and IL6RA. GATA2, but not 9aa-Ins, reversed elevated Il6st and Il6ra expression and IL-6/STAT3 signaling. ATAC-seq revealed accessible chromatin 24 kb and 30 kb upstream of Il6st in hi-77-/- cells or hi-77-/- with 9aa-ins, but not wild type cells or hi-77-/- rescued with GATA2. To ask whether these sites are enhancers mediating IL-6 signaling, CRISPR-Cas9 gene editing was used to delete the sequences in hi-77-/- cells. Il6st expression decreased 13-fold (P&amp;lt;0.0001) and IL-6/STAT3 signaling decreased 85% (P&amp;lt;0.0001). Thus, GATA2 deficiency commissions enhancers that elevate Il6st expression and IL-6 signaling. To determine whether GATA2 deficiency commissions enhancers essential for other GATA2-repressed cytokine/chemokine receptor genes, we analyzed accessible chromatin in hi-77-/- cells at all cytokine/chemokine receptor genes and identified prospective enhancers that are GATA2-, but not 9aa-Ins-, regulated. These included the Csf1r +2.6 kb enhancer (Rojo et al., 2019). As enhancer decommissioning has utility to discriminate GATA2 from a pathogenic variant, additional clinical variants are being analyzed. We are also analyzing whether variants are defective in utilizing transcription factors and coregulators (C/EBPε and SMARCD2 for activation and RUNX1 and PU.1 for repression) that functionally interact with GATA2 at enhancers, and are extending murine analyses to human with a GATA2+/- HUDEP2 erythroid progenitor rescue system. In aggregate, diverse metrics related to genome regulation, with and without inflammation, as well as subcellular localization and protein stability, are being used to innovate a machine learning-based classifier strategy to ascribe whether any variant most closely resembles GATA2 or pathogenic variants. Using a minimal metric cohort that rigorously segregates GATA2 from clinical variants, we will streamline assays to ensure rapid, yet definitive, variant curation, compatible with clinical decision making. This curation strategy is being extended to decipher genetic variation in other genes that create an MDS and AML predisposition.

  PublisherDOI

• Author response: Establishing And Maintaining The Blood-Brain Barrier: Epigenetic And Signaling Determinants

  2024-10-23

  peer-reviewOpen access

  The blood-brain barrier (BBB) controls the movement of molecules into and out of the central nervous system (CNS). Since a functional BBB forms by mouse embryonic day E15.5, we reasoned that gene cohorts expressed in CNS endothelial cells (EC) at E13.5 contribute to BBB formation. In contrast, adult gene signatures reflect BBB maintenance mechanisms. Supporting this hypothesis, transcriptomic analysis revealed distinct cohorts of EC genes involved in BBB formation and maintenance. Here, we demonstrate that epigenetic regulator’s histone deacetylase 2 (HDAC2) and polycomb repressive complex 2 (PRC2) control EC gene expression for BBB development and prevent Wnt/β-catenin (Wnt) target genes from being expressed in adult CNS ECs. Low Wnt activity during development modifies BBB genes epigenetically for the formation of functional BBB. As a Class-I HDAC inhibitor induces adult CNS ECs to regain Wnt activity and BBB genetic signatures that support BBB formation, our results inform strategies to promote BBB repair.

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• 3150 – GATA2 DETERMINES HEMATOPOIETIC STEM/PROGENITOR CELL RESPONSES TO OPPORTUNISTIC FUNGAL INFECTION

  Experimental Hematology · 2024-08-01

  articleSenior author
  PublisherDOI

• Pathogenic GATA2 genetic variants utilize an obligate enhancer mechanism to distort a multilineage differentiation program

  Proceedings of the National Academy of Sciences · 2024-02-29 · 6 citations

  articleOpen accessSenior authorCorresponding

  Mutations in genes encoding transcription factors inactivate or generate ectopic activities to instigate pathogenesis. By disrupting hematopoietic stem/progenitor cells, GATA2 germline variants create a bone marrow failure and leukemia predisposition, GATA2 deficiency syndrome, yet mechanisms underlying the complex phenotypic constellation are unresolved. We used a GATA2-deficient progenitor rescue system to analyze how genetic variation influences GATA2 functions. Pathogenic variants impaired, without abrogating, GATA2-dependent transcriptional regulation. Variants promoted eosinophil and repressed monocytic differentiation without regulating mast cell and erythroid differentiation. While GATA2 and T354M required the DNA-binding C-terminal zinc finger, T354M disproportionately required the N-terminal finger and N terminus. GATA2 and T354M activated a CCAAT/Enhancer Binding Protein-ε (C/EBPε) enhancer, creating a feedforward loop operating with the T-cell Acute Lymphocyte Leukemia-1 (TAL1) transcription factor. Elevating C/EBPε partially normalized hematopoietic defects of GATA2-deficient progenitors. Thus, pathogenic germline variation discriminatively spares or compromises transcription factor attributes, and retaining an obligate enhancer mechanism distorts a multilineage differentiation program.

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• 3182 – GENOMIC DETERMINANTS OF HEMATOPOIETIC PROGENITOR SENSITIVITY TO INNATE IMMUNE SIGNALING

  Experimental Hematology · 2024-08-01

  articleSenior author
  PublisherDOI

• Multiomic Analyses of Erythropoiesis and Anemia Mechanisms Reveal a Signaling Network with Converging Cytokine and Sphingolipid Inflammatory Pathways

  Blood · 2024-11-05

  articleSenior author

  Recent studies from our group have established a paradigm where GATA factors control erythropoiesis by regulating the expression of transporters and biosynthetic enzymes, which dictates intracellular levels of small molecules, including heme, metal ions, and sphingolipids. GATA1 controls the expression of sphingolipid metabolic enzymes, including Degs1 and Sphk1, which confer ceramide homeostasis during erythropoiesis. Disrupting ceramide (Cer) homeostasis impairs erythroid progenitor function and erythroblast survival by antagonizing critical stem cell factor (SCF) and erythropoietin (Epo) signaling via a PP2A-dependent mechanism. While Epo-induced AKT, ERK, and JAK/STAT signaling are attenuated by disrupting Cer homeostasis, the full spectrum of Epo/Cer-dependent signaling events and how such events integrate into the overall signaling milieu of the developing erythroblast in normal and pathological states is unknown. To comprehensively elucidate the components of the Epo/Cer-instigated signaling network, we performed phospho-proteomics in primary human HSPC-derived erythroblasts with or without short-term (5 min) Epo stimulation under normal conditions and conditions in which Cer disrupts function. Total cellular proteins were digested with lysyl endopeptidase, and phospho-peptides were enriched with titanium dioxide before liquid chromatography-mass spectrometry (LC-MS) analysis. Consistent with the established paradigm, pY694-STAT5A/B, the canonical target of Epo signaling, was the most highly upregulated phospho-peptide in response to Epo, and this upregulation was abolished by Cer. Differential analyses (|log2FoldChange|&amp;gt;0.5, p&amp;lt;0.05) revealed 268 Epo-regulated phospho-peptides, the majority of which had not been linked to Epo signaling. Of the 268 Epo-regulated phospho-peptides, Cer impaired or facilitated Epo-dependent regulation of 17. Thus, Cer impacts a specialized sector of the Epo signaling network. Of the 17 Epo/Cer-co-regulated phospho-peptides, Epo increased and Cer decreased pY694-STAT5A/B, while 14 were downregulated by Epo and upregulated by Cer, suggesting that Cer antagonizes Epo activity in most of these cases. These peptides include pS109-endosulfine alpha (ENSA), which is decreased 2.4-fold by Epo and increased 1.9-fold when Cer is present with Epo. ENSA, and its paralog cAMP-regulated phosphoprotein 19 (ARPP19), are endogenous regulators of PP2A activity and cell cycle progression. To ask if ENSA and/or ARPP19 mediate Epo signaling, we generated Ensa/Arpp19 double-knockout G1E-ER-GATA1 cells using CRISPR-Cas9 and quantified Epo signaling in WT and double-mutant cells. Depleting ENSA and ARPP19 enhanced Epo-dependent phosphorylation of STAT5, suggesting that ENSA/ARPP19 are new components of the Epo signaling pathway. An in-depth mechanistic analysis is being developed. Chronic inflammation is often associated with elevated inflammatory cytokines, disrupted ceramide homeostasis, and anemia. Treating primary human HSPCs ex vivo with a cocktail of inflammatory cytokines (TNFα, IFNγ, and IL-6) had little impact on the viability of erythroid progenitors at day 9 but significantly impaired generation and/or survival of glycophorin A (GPA)-positive immature erythroblasts at day 13, suggesting a differential sensitivity of cells at distinct stages of differentiation to inflammation. To elucidate the specific cell types and cadre of genes (and networks) that are hyper- or hypo-sensitive to inflammatory signaling and how sphingolipids contribute to this process, we performed single-cell RNA-sequencing (scRNA-seq) and quantitative lipidomics in primary human erythroid cells at day 9 and day 13 treated with or without the inflammatory cytokine cocktail. We are integrating the lipidomic and scRNA-seq data to establish mechanisms by which inflammation remodels the sphingolipidome, corrupts molecular networks, and dysregulates erythropoiesis at single-cell resolution. In summary, we established an integrated network involving cytokine signaling, inflammation, and sphingolipids that controls erythropoiesis through multiomic studies in primary human erythroid cells. These datasets are providing unique mechanistic insights into the control of erythropoiesis under normal and pathological conditions and translational applications for anemia of inflammation and potentially of broader impact.

  PublisherDOI

Recent grants

• Cancer Center Administration

  NIH · $99.8M · 1997–2028

• Hematopoietic Regulation via GATA Switches

  NIH · $7.5M · 2006–2029

• NIH Grant R01ES003980

  NIH · $1.4M · 1996

• NIH Grant R01HL116365

  NIH · $1.6M · 2016

• NIH Grant R56DK068634

  NIH · $109k · 2006

Frequent coauthors

• Kirby D. Johnson

  University of Wisconsin Carbone Cancer Center

  200 shared

• Koichi R. Katsumura

  Cancer Research Institute

  92 shared

• Alexandra A. Soukup

  80 shared

• Sündüz Keleş

  78 shared

• Charu Mehta

  University of Wisconsin Carbone Cancer Center

  59 shared

• Rajendran Sanalkumar

  University of Lausanne

  57 shared

• Xin Gao

  Jilin University

  53 shared

• Kyle J. Hewitt

  University of Nebraska Medical Center

  47 shared

Education

• Ph.D., Molecular and Cell Biology

  University of California, San Francisco

  1994

• B.S., Molecular and Cell Biology

  University of California, Berkeley

  1989