About

Dr. Yali Dou is a Professor in the Department of Medicine and Department of Biochemistry and Molecular Medicine at the Keck School of Medicine of USC. She holds the Marion and Harry Keiper Endowed Chair in Cancer Research and serves as the Associate Director for Basic Science at the Norris Comprehensive Cancer Center. Her research interests focus on cell fate decisions controlled by transcription factors and epigenetic regulators, including enzymes that carry out histone post-translational modifications. Her lab studies the establishment and maintenance of gene regulatory networks, emphasizing how chromatin modifications influence gene regulation through transcription factors and DNA regulatory elements. The research also explores the interactions between chromatin modifications and cellular processes such as metabolic regulation, genome stability, and higher-order chromatin organization, with extensive work on the MLL/KMT2 family of histone methyltransferases. These enzymes deposit histone H3 lysine 4 methylation, which marks active gene promoters and enhancers, and are frequently mutated or translocated in various cancers and developmental syndromes. Her work aims to deepen understanding of epigenetic modulators in development and disease, and to inform the development of targeted therapies for cancer and regenerative medicine.

Research topics

• Biology
• Cancer research
• Cell biology
• Computer Science
• Genetics
• Immunology

Selected publications

• PTP4A2 Promotes Leukemogenesis through Inhibiting the p53 Tumor Suppressor Signaling Pathway in Leukemia-initiating Cells

  Blood Advances · 2026-04-15

  articleOpen access

  Acute myeloid leukemia (AML) is an aggressive hematological malignancy that is sustained by leukemia-initiating cells (LICs). While PTP4A2 phosphatase, as known as PRL2, is highly expressed in AML, the mechanisms by which PTP4A2 promotes leukemogenesis are largely unexplored. In this study, we demonstrate that PTP4A2 promotes AML by inhibiting the p53 tumor suppressor pathway in LICs. Using KMT2A-MLLT3-driven AML as a model, we found that PTP4A2 deficiency activates p53 and induces LIC apoptosis and senescence, thereby extending the survival of recipient mice repopulated with Ptp4a2-/- LICs. Mechanistically, PTP4A2 directly interacts with p53 and dephosphorylates it at serine 392, decreasing p53 stability and activity to enhance LIC proliferation and survival. Collectively, our findings identify p53 as a potential PTP4A2 substrate in leukemia cells and uncover a novel mechanism by which PTP4A2 enhances LIC maintenance.

  PublisherOA PDFDOI

• Revealing long-range heterogeneous organization of nucleoproteins with 6mA footprinting by ipdTrimming

  Genome biology · 2025-05-21 · 1 citations

  articleOpen accessSenior author

  -methyladenine (6mA) footprinting is a transformative methodology for revealing the heterogenous and dynamic distribution of nucleosomes and other DNA-binding proteins. Here, we present ipdTrimming, a novel 6mA-calling pipeline that outperforms existing tools in both computational efficiency and accuracy. Utilizing this optimized experimental and computational framework, we are able to map nucleosome positioning and transcription factor occupancy in nuclear DNA and establish high-resolution, long-range binding events in mitochondrial DNA. Our study highlights the potential of 6mA footprinting to capture coordinated nucleoprotein binding and to unravel epigenetic heterogeneity.

  PublisherOA PDFDOI

• Division of labor among H3K4 methyltransferases defines distinct facets of homeostatic plasticity

  Cell Reports · 2025-05-21

  articleOpen access

  Heterozygous mutations in any of the six H3K4 methyltransferases (KMT2s) result in monogenic neurodevelopmental disorders, indicating non-redundant yet poorly understood roles of this enzyme family in neurodevelopment. However, the specific cellular role of KMT2 enzymes in the brain remains poorly understood, owing to the clear non-catalytic functions of each family member and the potential for functional redundancy in installing H3K4 methylation (H3K4me). Here, we identify an instructive role for H3K4me in controlling synapse function and a division of labor among the six KMT2 enzymes in regulating homeostatic synaptic scaling. Using RNAi screening, conditional genetics, small-molecule inhibitors, and transcriptional profiling, our data reveal that individual KMT2 enzymes have unique roles and operate in specific phases to control distinct facets of homeostatic scaling. Together, our results suggest that the expansion of this enzyme family in mammals is key to coupling fine-tuned gene expression changes to adaptive modifications of synaptic function.

  PublisherOA PDFDOI

• Abstract 4845: The MLL3/GRHL2 complex modulates early malignant development and anti-tumor immunity in upper aerodigestive squamous cell carcinoma

  Cancer Research · 2025-04-21

  article

  Abstract Upper aerodigestive squamous cell carcinoma (UASCC), including head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC), poses substantial challenges in clinical care due to its aggressive behavior and poorly understood mechanisms of early malignant transformation. This study investigates the role of MLL3 mutations as critical, clonal genomic events driving UASCC tumorigenesis. Using CRISPR-edited organoid models across species, we demonstrate that MLL3 loss facilitates early squamous neoplastic evolution. Additionally, we uncover an MLL3/GRHL2 protein complex that orchestrates epigenomic regulation, particularly influencing immune-related pathways. Strikingly, we identify a novel MLL3/GRHL2-IRF1 axis that induces the expression of Th1 chemokines, such as CXCL9 and CXCL10, enhancing anti-tumor immunity by promoting T cell infiltration within the tumor microenvironment. In syngeneic mouse models, including both subcutaneous and orthotopic settings, MLL3 was shown to modulate the efficacy of immune checkpoint blockade (ICB) therapy. Consistently, clinical data from human patients demonstrate a robust correlation between MLL3 expression and responsiveness to ICB therapy. This study underscores the pivotal role of MLL3 in UASCC pathogenesis and highlights the therapeutic potential of targeting the MLL3/GRHL2-mediated immune response pathways to improve outcomes in UASCC treatment. Citation Format: Chehyun Nam, Guowei Huang, Yueyuan Zheng, Hua Zhao, Ethan Pan, Boyan Hu, Talia Wenger, Hieu Van, Liyan Xu, En-min Li, H.Phillip Koeffler, Kai Ge, Yali Dou, Uttam K. Sinha, Young Min Park, De-Chen Lin. The MLL3/GRHL2 complex modulates early malignant development and anti-tumor immunity in upper aerodigestive squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4845.

  PublisherDOI

• Mutant p53 promotes clonal hematopoiesis by generating a chronic inflammatory microenvironment

  Journal of Clinical Investigation · 2025-12-30 · 3 citations

  articleOpen access

  Older individuals with somatic TP53 mutations manifest clonal hematopoiesis (CH) and are at high risk of developing myeloid neoplasms. However, the underlying mechanisms are not fully understood. Here, we show that inflammatory stress confers a competitive advantage to p53 mutant hematopoietic stem and progenitor cells (HSPCs) by activating the NLRP1 inflammasome and increasing the secretion of pro-inflammatory cytokines such as IL-1β, inhibiting WT HSPC fitness in a paracrine fashion. During aging, mutant p53 dysregulates pre-mRNA splicing in HSPCs, leading to enhanced NF-κB activation and increased secretion of IL-1β and IL-6, thereby generating a chronic inflammatory bone marrow microenvironment. Furthermore, blocking IL-1β with IL-1β neutralizing antibody or inhibiting IL-1β secretion using gasdermin D inhibitor decreases the fitness of p53 mutant HSPCs. Thus, our findings uncover an important role for mutant p53 in regulating inflammatory signaling in CH and suggest that curbing inflammation may prevent the progression of TP53-mutant CH to myeloid neoplasms.

  PublisherOA PDFDOI

• One-carbon metabolism in cancer: moonlighting functions of metabolic enzymes and anti-tumor therapy

  Cancer and Metastasis Reviews · 2025-12-13 · 2 citations

  reviewOpen access
  PublisherOA PDFDOI

• The FBXW7–KMT2 axis in cancer-associated fibroblasts controls tumor growth via an epigenetic-paracrine mechanism

  Proceedings of the National Academy of Sciences · 2025-03-24 · 7 citations

  articleOpen access

  F-box and WD repeat domain-containing 7 (FBXW7) is a tumor suppressor that targets various oncoproteins for degradation, but its role in modulating cancer-associated fibroblasts (CAFs) in the tumor microenvironment remains elusive. Here, we report that FBXW7 expression is gradually downregulated in CAFs during the progression of human pancreatic and lung cancers. Mechanically, FBXW7 inhibits histone lysine methyltransferase 2 (KMT2) methyltransferase activity via retinoblastoma binding protein 5 (RbBP5) binding, whereas FBXW7 depletion abrogates the binding to activate KMT2, leading to increased H3K4 methylations and global upregulation of gene expression. Activation of the interleukin-17 (IL-17) signaling pathway triggers the secretion of cytokines and chemokines to promote migration, invasion, and sphere formation of lung cancer cells. Coinjection of Fbxw7-depleted mouse embryonic fibroblasts with cancer cells enhances in vivo tumor growth, demonstrating a paracrine effect. Hypoxia downregulates CAF FBXW7 via ETS proto-oncogene 1 (ETS1) to increase H3K4 methylation, whereas conditioned media from hypoxia-exposed CAFs promotes migration and invasion of pancreatic cancer cells, highlighting FBXW7's tumor-suppressing role through KMT2 inactivation.

  PublisherOA PDFDOI

• Abstract A008: Epigenetic dynamics in KMT2A-amplified leukemia

  Cancer Research · 2025-02-01

  articleSenior author

  Abstract The lysine methyltransferase KMT2A/MLL1 plays a crucial role in normal development and hematopoiesis. Rearrangement of KMT2A results in the formation of a KMT2A fusion protein with aberrant activity, which is a well-characterized driver of leukemogenesis and is therapeutically targetable. In contrast to the widely studied KMT2A translocation, the molecular consequences of other KMT2A alterations, including KMT2A amplification, remain unknown. KMT2A amplification is detected in highly aggressive and treatment-resistant myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). It strongly associates with TP53 mutations and complex karyotypes. Unlike KMT2A rearrangement, KMT2A amplification is reported mostly in patients older than 65 and treated with alkylating agents. Here, we conducted a comprehensive molecular analysis of KMT2A-amplified MDS/AML by long-read nanopore sequencing. We have revealed the unique epigenetic landscape, including DNA methylation, histone modification, and chromatin accessibility, associated with KMT2A amplification. We also explored the potential of targeting KMT2A or KMT2A-medicated pathways to block leukemogenesis. These results provide a foundation for targeting the KMT2A complex in KMT2A-amplified disease, representing a promising first step toward treating MDS/AML associated with KMT2A amplification. Citation Format: Jayme Ogino, Yang Liu, Wentao Yang, Madina Sukhanova, Sheng Li, Yali Dou. Epigenetic dynamics in KMT2A-amplified leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr A008.

  PublisherDOI

• A micro-metabolic rewiring assay for assessing hypoxia-associated cancer metabolic heterogeneity

  Bioactive Materials · 2025-02-27 · 4 citations

  articleOpen access

  Cancer metabolism plays an essential role in therapeutic resistance, where significant inter- and intra-tumoral heterogeneity exists. Hypoxia is a prominent driver of metabolic rewiring behaviors and drug responses. Recapitulating the hypoxic landscape in the tumor microenvironment thus offers unique insights into heterogeneity in metabolic rewiring and therapeutic responses, to inform better treatment strategies. There remains a lack of scalable tools that can readily interface with imaging platforms and resolve the heterogeneous behaviors in hypoxia-associated metabolic rewiring. Here we present a micro-metabolic rewiring (μMeRe) assay that provides the scalability and resolution needed to characterize the metabolic rewiring behaviors of different cancer cells in the context of hypoxic solid tumors. Our assay generates hypoxia through cellular metabolism without external gas controls, enabling the characterization of cell-specific intrinsic ability to drive hypoxia and undergo metabolic rewiring. We further developed quantitative metrics that measure the metabolic plasticity through phenotypes and gene expression. As a proof-of-concept, we evaluated the efficacy of a metabolism-targeting strategy in mitigating hypoxia- and metabolic rewiring-induced chemotherapeutic resistance. Our study and the scalable platform thus lay the foundation for designing more effective cancer treatments tailored toward specific metabolic rewiring behaviors. • An assay is established to measure cancer-specific response to an oxygen-limited TME. • Cancer cells possess distinct capability in driving a hypoxic TME and undergo rewiring. • Cancer-specific HIF response traits underlie distinct metabolic rewiring behaviors. • Mitochondrial complex inhibition is especially effective against cells driving severe hypoxia.

  PublisherDOI

• The MLL3/GRHL2 complex regulates malignant transformation and anti-tumor immunity in squamous cancer

  The Journal of Experimental Medicine · 2025-02-18 · 3 citations

  articleOpen access

  Upper aerodigestive squamous cell carcinoma (UASCC) presents significant challenges in clinical management due to its aggressive nature. Here, we elucidate the role of MLL3 mutations as early, clonal genomic events in UASCC tumorigenesis, highlighting their role as foundational drivers of cancer development. Utilizing CRISPR-edited, cross-species organoid modeling, we demonstrate that loss of MLL3 contributes to early squamous neoplastic evolution. Furthermore, we identify an MLL3/GRHL2 protein complex that regulates the UASCC epigenome, particularly impacting immune response pathways. Notably, a novel MLL3/GRHL2-IRF1 axis promotes the expression of Th1 chemokines, enhancing anti-tumor immunity by facilitating T cell infiltration into the tumor microenvironment. Consequently, MLL3 regulates the in vivo efficacy of immune checkpoint blockade (ICB) therapy, corroborated by the strong association between MLL3 expression and human patients' clinical response to ICB therapy. Our work underscores the significance of MLL3 in UASCC pathogenesis and highlights the interplay between MLL3/GRHL2 and immune response pathways as potential therapeutic targets for UASCC treatment.

  PublisherOA PDFDOI

Recent grants

• Targeting the MLL-WDR5 protein-protein interaction

  NIH · $1.8M · 2013–2018

• Function of MLL in transcription regulation

  NIH · $4.0M · 2009–2025

• Enhancer Dysregulation in AML

  NIH · $2.7M · 2019–2025

• Cancer Research Training and Education Coordination

  NIH · $67.7M · 1996–2026

• Structural insights into the MLL core complexes

  NIH · $3.0M · 2020–2026

Frequent coauthors

• Robert G. Roeder

  Rockefeller University

  76 shared

• Jay L. Hess

  University of Michigan–Ann Arbor

  58 shared

• Thomas A. Milne

  University of Oxford

  50 shared

• Denise Gibbs

  Temple University

  36 shared

• Matthew Meyerson

  Dana-Farber Cancer Institute

  36 shared

• Christina M. Hughes

  36 shared

• Robert W. Schnepp

  36 shared

• Virginia A. LiVolsi

  Hospital of the University of Pennsylvania

  36 shared

Awards & honors

• Leukemia & Lymphoma Society Scholar Award (2012)
• Stand Up to Cancer IRG Award (2011)
• AACR Gertrude B. Elion Cancer Research Award (2010)
• Dean’s Award in Basic Science at University of Michigan (201…
• AAAS Fellow (2025)