A5065868457- Acute Myeloid Leukemia Research
- RNA Interference and Gene Delivery
- interferon and immune responses
- Protein Degradation and Inhibitors
- Mosquito-borne diseases and control
- CAR-T cell therapy research
- Genomics and Chromatin Dynamics
- Immunodeficiency and Autoimmune Disorders
- RNA modifications and cancer
- Immune Cell Function and Interaction
- Cancer-related molecular mechanisms research
- RNA and protein synthesis mechanisms
- Biochemical and Molecular Research
- Single-cell and spatial transcriptomics
- Antibiotic Resistance in Bacteria
- RNA Research and Splicing
- Epigenetics and DNA Methylation
- Pneumonia and Respiratory Infections
- Advanced biosensing and bioanalysis techniques
- Extracellular vesicles in disease
- Ubiquitin and proteasome pathways
- CRISPR and Genetic Engineering
- HIV/AIDS drug development and treatment
- Histone Deacetylase Inhibitors Research
- Bacterial biofilms and quorum sensing
Dana-Farber Cancer Institute
2019-2024
Dana-Farber/Boston Children's Cancer and Blood Disorders Center
2021-2023
Harvard University
2019-2023
Boston Children's Hospital
2019-2023
Broad Institute
2019-2023
Massachusetts Institute of Technology
2022-2023
Children's Hospital of Philadelphia
2012-2014
Children's Hospital of Pittsburgh
2014
University of Pittsburgh
2014
Fox Chase Cancer Center
2006-2009
ABSTRACT A total of 904 consecutive nosocomial isolates Escherichia coli and Klebsiella pneumoniae collected from 28 Russian hospitals were screened for production extended-spectrumβ -lactamases (ESBLs). The ESBL phenotype was detected in 78 (15.8%) E. 248 (60.8%) K. isolates. One hundred fifteen carried the genes CTX-M-type β-lactamases, which, as shown by PCR-restriction fragment length polymorphism analysis, distributed into two genetic groups CTX-M-1 (93%)- CTX-M-2 (7%)-related enzymes....
Combinatorial actions of relatively few transcription factors control hematopoietic differentiation. To investigate this process in erythro-megakaryopoiesis, we correlated the genome-wide chromatin occupancy signatures four master (GATA1, GATA2, TAL1, and FLI1) three diagnostic histone modification marks with gene expression changes that occur during development primary cultured megakaryocytes (MEG) erythroblasts (ERY) from murine fetal liver stem/progenitor cells. We identified a robust,...
We used mouse ENCODE data along with complementary from other laboratories to study the dynamics of occupancy and role in gene regulation transcription factor TAL1, a critical regulator hematopoiesis, at multiple stages hematopoietic differentiation. combined ChIP-seq RNA-seq six cell types representing progression multilineage precursors differentiated erythroblasts megakaryocytes. found that sites shift dramatically during commitment erythroid lineage, vary further terminal maturation, are...
Leukemic blasts are immune cells gone awry. We hypothesized that dysregulation of inflammatory pathways contributes to the maintenance their leukemic state and can be exploited as cell-intrinsic, self-directed immunotherapy. To this end, we applied genome-wide screens discover genetic vulnerabilities in acute myeloid leukemia (AML) implicated pathways. identified modulator IRF2BP2 a selective AML dependency. validated cell dependency on with protein degradation approaches vitro genetically...
rRNAs are transcribed from ribosomal DNA (rDNA) repeats, the most intensively loci in genome. Due to their repetitive nature, there is a lack of genome assemblies suitable for rDNA mapping, creating vacuum our understanding how abundant RNA cell regulated. Our recent work revealed binding numerous mammalian transcription and chromatin factors rDNA. Several these were known play critical roles development, tissue function, malignancy, but potential regulation remained unexplored. This...
Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyses the rate-limiting step in guanine nucleotide biosynthesis. IMPDH has an evolutionary conserved CBS subdomain of unknown function. The can be deleted without impairing vitro catalytic activity and is site for mutations associated with human retinitis pigmentosa. A guanine-prototrophic Escherichia coli strain, MP101, was constructed sequence from chromosomal gene IMPDH. ATP content substantially elevated MP101 whereas GTP slighty...
Acute myeloid leukemia with KMT2A (MLL) rearrangements is characterized by specific patterns of gene expression and enhancer architecture, implying unique core transcriptional regulatory circuitry. Here, we identified the transcription factors MEF2D IRF8 as selective dependencies KMT2A-rearranged AML, where displays partially redundant functions its paralog, MEF2C. Rapid factor degradation followed measurements genome-wide rates superresolution microscopy revealed that form a distinct module...
The Bateman domain (CBS subdomain) of IMP dehydrogenase (IMPDH), a rate-limiting enzyme the de novo GMP biosynthesis, is evolutionarily conserved but has no established function. Deletion effect on in vitro IMPDH activity. We report that vivo deletion Escherichia coli (guaBΔCBS) sensitizes bacterium to growth arrest by adenosine and inosine. These nucleosides exert their inhibitory via dramatic increase intracellular adenylate nucleotide pool, which results enhanced allosteric inhibition...
Abstract Relapse of acute myeloid leukemia (AML) after allogeneic bone marrow transplantation has been linked to immune evasion due reduced expression major histocompatibility complex class II (MHCII) genes through unknown mechanisms. In this work, we developed CORENODE, a computational algorithm for genome-wide transcription network decomposition that identified factor (TF) tetrad consisting IRF8, MYB, MEF2C, and MEIS1, regulating MHCII in AML cells. We show at relapse is transcriptionally...
ABSTRACT Thirty-four cefotaxime-resistant Salmonella enterica serovar Typhimurium isolates representative of the that caused outbreaks gastroenteritis in 10 hospitals seven regions Russia and Belarus from 1994 to 2003 were analyzed. All produced CTX-M-5-like extended-spectrum β-lactamase, which confers high-level resistance cefotaxime ceftriaxone decreased susceptibility ceftazidime. The bla CTX-M genes located on small (7.4- 12-kb) non-self-transferable plasmids approximately 20 bp...
High-risk forms of B-acute lymphoblastic leukemia (B-ALL) remain a therapeutic challenge. Leukemia-initiating cells (LICs) self-renew and spark relapse therefore have been the subject intensive investigation; however, properties LICs in high-risk B-ALL are not well understood. Here, we use single-cell transcriptomics quantitative xenotransplantation to understand MLL-rearranged (MLL-r) B-ALL. Compared with reported LIC frequencies acute myeloid (AML), engraftable MLL-r abundant. Although...
This chapter contains sections titled: Overview of IMPDH Kinetic Mechanism and Substrate Interactions Chemical Protein Conformational Flexibility Water Activation Species-Specific Drug Selectivity Monovalent Cation Subdomain Conclusions Acknowledgments References
Abstract Background The detection of unknown mutations is important in research and medicine. For this purpose, a mismatch-specific endonuclease CEL I from celery has been established as useful tool high throughput projects. Previously, I-like activities were described only variety plants could not be expressed an active form bacteria. Results We describe expression recombinant plant mismatch endonucleases modification their activities. also report the cloning ortholog Spinacia oleracea...
ABSTRACT We report on a novel CTX-M extended-spectrum β-lactamase (ESBL), designated CTX-M-42, with enhanced activity toward ceftazidime. CTX-M-42 was identified in hypermutable Escherichia coli nosocomial isolate (isolate Irk2320) and is Pro167Thr amino acid substitution variant of CTX-M-3. By molecular typing ESBL-producing E. strains previously isolated the same hospital ward, we were able to identify putative progenitor (strain Irk1224) Irk2320, which had mutator phenotype harbored...
FISH-Flow (fluorescence in situ hybridization-flow cytometry) involves hybridizing fluorescent oligos to RNA and quantifying fluorescence at a single-cell level using flow cytometry. Here, we present protocol quantify nascent 47S mature 18S 28S rRNAs mouse human cells, including rRNA quantification across cell cycle stages DNA staining. We describe steps for preparation, hybridization of probes against rRNA, then detail procedures cytometry data analysis. For complete details on the use...
Lineage-defining transcription factors form densely interconnected circuits in chromatin occupancy assays, but the functional significance of these networks remains underexplored. We reconstructed topology a leukemia cell network from direct gene-regulatory programs eight core transcriptional regulators established pre-steady state assays coupling targeted protein degradation with nascent transcriptomics. The displayed narrow, largely non-overlapping programs, forming sparsely hierarchy...
Attenuating aberrant transcriptional circuits holds great promise for the treatment of numerous diseases, including cancer. However, development inhibitors is hampered by lack a generally accepted functional cellular readout to characterize their target specificity and on-target activity. We benchmarked direct gene-regulatory signatures six agents reported as oncogenic transcription factor MYB against targeted degradation in nascent transcriptomics assay. The demonstrated partial genes but...
ABSTRACT Ribosomal RNAs (rRNAs) are transcribed from rDNA repeats, the most intensively loci in genome. Due to their repetitive nature, there is a lack of genome assemblies suitable for mapping, creating vacuum our understanding how abundant RNA cell regulated. Our recent work 1 revealed binding numerous mammalian transcription and chromatin factors rDNA. Several these were known play critical roles development, tissue function, malignancy, but potential had remained unexplored. demonstrated...