A5050851135- Acute Myeloid Leukemia Research
- Acute Lymphoblastic Leukemia research
- Epigenetics and DNA Methylation
- Hematopoietic Stem Cell Transplantation
- Protein Degradation and Inhibitors
- Immune Cell Function and Interaction
- Cancer Genomics and Diagnostics
- Childhood Cancer Survivors' Quality of Life
- Lymphoma Diagnosis and Treatment
- Pharmaceutical studies and practices
- CAR-T cell therapy research
- Genomics and Chromatin Dynamics
- Cancer therapeutics and mechanisms
- Immune cells in cancer
- Genomics and Rare Diseases
- Chronic Lymphocytic Leukemia Research
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Single-cell and spatial transcriptomics
- Eosinophilic Disorders and Syndromes
- Erythrocyte Function and Pathophysiology
- Renal and related cancers
- Prostate Cancer Treatment and Research
- interferon and immune responses
- Multiple Myeloma Research and Treatments
- Cancer-related gene regulation
Washington University in St. Louis
2015-2024
SickKids Foundation
2024
Hospital for Sick Children
2024
St. Louis Children's Hospital
2021-2023
Saint Louis University
2023
The University of Texas Southwestern Medical Center
2012-2014
The homeodomain-containing transcription factor NKX3.1 is a putative prostate tumor suppressor that expressed in largely prostate-specific and androgen-regulated manner. Loss of protein expression common human carcinomas prostatic intraepithelial neoplasia (PIN) lesions correlates with progression. Disruption the murine Nkx3.1 gene results defects branching morphogenesis, secretions, growth. To more closely mimic pattern loss occurs tumors, we have used Cre- loxP-mediated recombination to...
Abstract Background Emerging RNA viruses that target the central nervous system (CNS) lead to cognitive sequelae in survivors. Studies humans and mice infected with West Nile virus (WNV), a re-emerging associated learning memory deficits, revealed microglial-mediated synapse elimination within hippocampus. Moreover, CNS-resident T (T R M) cells activate microglia, limiting recovery inducing spatial defects WNV-recovered mice. The signals involved cell-microglia interactions are unknown....
Androgen signaling via the androgen receptor (AR) transcription factor is crucial to normal prostate homeostasis and tumorigenesis. Current models of AR function are predominantly based on studies prostate-specific antigen regulation in androgen-responsive cell lines. To expand these vitro paradigms, we used mouse elucidate mechanisms through which regulates another direct target, FKBP5, vivo. FKBP5 encodes an immunophilin that has been previously implicated glucocorticoid progestin pathways...
Despite a remarkable increase in the genomic profiling of cancer, integration discoveries into clinical care has lagged behind. We report feasibility rapid identification targetable mutations 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on prospective trial conducted by LEAP Consortium. Eighteen percent had high confidence Tier 1 2 recommendation. describe responses 14% leukemia who received matched targeted therapy. Further, order to inform future therapy...
MLL rearrangements ( r) are the most common cause of congenital and infant leukemias. r arise prior to birth require few cooperating mutations for transformation, yet leukemias 10-fold less than >100-fold childhood overall. This raises question whether mechanisms exist suppress leukemic transformation during fetal life, thereby protecting developing fetus from malignancy a period rapid hematopoietic progenitor expansion. Here, we use mouse models show that MLL::ENL exposure creates...
An important aspect of understanding a biological pathway is to delineate the transcriptional regulatory mechanisms genes involved. Two tasks are often encountered when studying transcription regulation, i.e., (1) identification common regulators set coexpressed genes; (2) that regulated by one or several factors. In this study, systematic and statistical approach was taken accomplish these establishing an integrated model considering all promoters characterized factors (TFs) in genome. A...
Adult hematopoietic stem cell (HSC) self-renewal requires precise control of protein synthesis, but fetal and adult HSCs have distinct mechanisms lineage outputs. This raises the question whether synthesis rates change with age. Here, we show that decline during HSC ontogeny, yet erythroid increase. A ribosomal mutation impairs ribosome biogenesis (Rpl24Bst/+) disrupts both self-renewal. However, Rpl24Bst/+ selectively erythropoiesis at differentiation stages exhibit fetal-specific...
The FLT3 Internal Tandem Duplication (FLT3ITD) mutation is common in adult acute myeloid leukemia (AML) but rare early childhood AML. It not clear why this difference occurs. Here we show that Flt3ITD and cooperating Flt3ITD/Runx1 mutations cause hematopoietic stem cell depletion progenitor expansion during fetal stages of murine development. In progenitors, FLT3ITD simultaneously induces self-renewal commitment programs via STAT5-dependent STAT5-independent mechanisms, respectively. While...
MLL-rearrangements (MLL-r) are recurrent genetic events in acute myeloid leukemia (AML) and frequently associate with poor prognosis. In infants, MLL-r can be sufficient to drive transformation. However, despite the prenatal origin of these patients, congenital is very rare transformation usually occurring postnatally. The influence signals on leukemogenesis, such as those mediated by fetal-specific protein LIN28B, remains controversial. Here, using a dual-transgenic mouse model that...
The myeloid tumor suppressor KMT2C is recurrently deleted in myelodysplastic syndrome (MDS) and acute leukemia (AML), particularly therapy-related MDS/AML (t-MDS/t-AML), as part of larger chromosome 7 deletions. Here, we show that deletions convey a selective advantage to hematopoietic stem cells (HSCs) after chemotherapy treatment may precipitate t-MDS/t-AML. Kmt2c markedly enhance murine HSC self-renewal capacity without altering proliferation rates. Haploid only when HSCs are driven into...
The role of polyunsaturated fatty acid (PUFA) biosynthesis in acute myeloid leukemia (AML) remains largely undefined. A comparative expression analysis 35 genes encoding enzymes showed that desaturase 1 (FADS1) was highly expressed across multiple AML subtypes relative to healthy controls and elevated FADS1 correlates with worse overall patient survival. Functionally, shRNA-mediated inhibition reduced cell growth vitro significantly delayed onset an mouse model. lines depleted arrested the...
Pten negatively regulates the phosphatidylinositol 3-kinase (PI3K) pathway and is required to maintain quiescent adult hematopoietic stem cells (HSCs). has been proposed regulate HSCs cell autonomously non-cell autonomously, but relative importance of each mechanism not directly tested. Furthermore, cytokines that activate PI3K upstream are well defined. We sought clarify whether or HSC mobilization. also tested deficiency affects response granulocyte colony-stimulating factor (G-CSF)...
Abstract MLL rearrangements are translocation mutations that cause both acute lymphoblastic leukemia and myeloid (AML). These translocations can occur as sole clonal driver in infant leukemias, suggesting fetal or neonatal hematopoietic progenitors may be exquisitely sensitive to transformation by fusion proteins. To test this possibility, we used transgenic mice induce one product, MLL-ENL, during fetal, neonatal, juvenile adult stages of life. When MLL-ENL was induced mice, almost all died...
Abstract Acute myeloid leukemia (AML) initiation requires multiple rate-limiting mutations to cooperatively reprogram progenitor cell identity. For example, FLT3 internal tandem duplication (FLT3ITD) cooperate with a variety of different initiating fate. These often skew toward either pediatric or adult AML patient populations, though FLT3ITD itself occurs at similar frequencies in both age groups. This raises the question whether might induce distinct transcriptional programs and unmask...
Type I interferon (IFN-1) regulates gene expression and hematopoiesis both during development in response to inflammatory stress. We previously showed that mice, hematopoietic stem cells (HSCs) multipotent progenitors (MPPs) induce IFN-1 target genes shortly before birth. This coincides with the onset of a transition adult hematopoiesis, it drives associated antigen presentation. However, is not clear whether perinatal modulates output, as has been observed contexts inflammation. have...