A5081137671- Acute Myeloid Leukemia Research
- Epigenetics and DNA Methylation
- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- Cancer Genomics and Diagnostics
- Hemoglobinopathies and Related Disorders
- RNA Research and Splicing
- RNA modifications and cancer
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Genomics and Chromatin Dynamics
- DNA Repair Mechanisms
- Single-cell and spatial transcriptomics
- Cancer-related gene regulation
- Cell Adhesion Molecules Research
- CRISPR and Genetic Engineering
- Genetic Associations and Epidemiology
- Chronic Lymphocytic Leukemia Research
- Blood disorders and treatments
- Genomic variations and chromosomal abnormalities
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Immunodeficiency and Autoimmune Disorders
- Drug Transport and Resistance Mechanisms
- Circadian rhythm and melatonin
- Peptidase Inhibition and Analysis
Dana-Farber Cancer Institute
2018-2024
Broad Institute
2018-2019
Harvard University
2013-2019
Massachusetts Institute of Technology
2019
Brigham and Women's Hospital
2011-2019
Washington State University
2002
Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence an expanded somatic blood-cell clone in persons without other hematologic abnormalities, common among older and associated with increased risk cancer. We previously found preliminary evidence for association between CHIP atherosclerotic cardiovascular disease, but nature this was unclear.
Lenalidomide is a drug with clinical efficacy in multiple myeloma and other B cell neoplasms, but its mechanism of action unknown. Using quantitative proteomics, we found that lenalidomide causes selective ubiquitination degradation two lymphoid transcription factors, IKZF1 IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF3 are essential factors myeloma. A single amino acid substitution conferred resistance to lenalidomide-induced rescued inhibition growth. Similarly, interleukin-2 production T...
Thrombosis in myeloproliferative neoplasms is associated with increased NETosis that can be targeted JAK inhibitors.
TP53, which encodes the tumor suppressor p53, is most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, are enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We used CRISPR-Cas9 to generate isogenic leukemia cell lines of common TP53 mutations. Functional, DNA-binding, transcriptional analyses revealed loss function but no GOF effects. Comprehensive scanning p53 single-amino acid...
There is a growing body of evidence that therapy-related myeloid neoplasms (t-MNs) with driver gene mutations arise in the background clonal hematopoiesis (CH) under positive selective pressure chemo- and radiation therapies. Uncovering exposure relationships provide advantage to specific CH critical understanding pathogenesis etiology t-MNs. In systematic analysis 416 patients t-MN detailed prior history, we found TP53 were significantly associated treatment thalidomide analogs,...
Research Article6 March 2017Open Access Transparent process Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially concert with TP53 mutations Ram Ajore Hematology and Transfusion Medicine, Department Laboratory Lund University, Lund, Sweden Search for more papers by this author David Raiser Brigham Women's Hospital, Harvard Medical School, Boston, MA, USA Marie McConkey Magnus Jöud Bernd Boidol Brenton Mar Gordon Saksena Broad Institute, 7 Cambridge...
Despite extensive insights into the underlying genetics and biology of acute myeloid leukemia (AML), overall survival remains poor new therapies are needed. We found that casein kinase 1 α (Csnk1a1), a serine-threonine kinase, is essential for AML cell in vivo. Normal hematopoietic stem progenitor cells (HSPCs) were relatively less affected by shRNA-mediated knockdown Csnk1a1. To identify downstream mediators Csnk1a1 critical cells, we performed an vivo pooled shRNA screen gene expression...
Abstract PPM1D encodes a phosphatase that is recurrently activated across cancer, most notably in therapy-related myeloid neoplasms. However, the function of hematopoiesis and its contribution to tumor cell growth remain incompletely understood. Using conditional mouse models, we uncover central role for Ppm1d validate potential as therapeutic target. We find regulates competitive fitness self-renewal hematopoietic stem cells (HSCs) with without exogenous genotoxic stresses. also show...
Other than hydroxyurea, no pharmacologic agents are clinically available for fetal hemoglobin (HbF) induction in sickle cell disease (SCD). An optimal candidate would induce HbF without causing cycle inhibition and act independently of hydroxyurea order to yield additional when combined. We explored whether histone deacetylase (HDAC) 1 or HDAC2 could achieve these goals. In human erythroid progenitor cells, shRNA knockdown the HDAC1 genes induced gamma globin, altering cellular proliferation...