Matthew Leventhal
A5002405280- Multiple Myeloma Research and Treatments
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Acute Myeloid Leukemia Research
- Advanced Breast Cancer Therapies
- Cancer-related Molecular Pathways
- Breast Cancer Treatment Studies
- Chronic Myeloid Leukemia Treatments
- Protein Degradation and Inhibitors
- Cancer Genomics and Diagnostics
- Epigenetics and DNA Methylation
- Alzheimer's disease research and treatments
- Cancer Treatment and Pharmacology
- Genetics, Aging, and Longevity in Model Organisms
- Immune Cell Function and Interaction
- RNA Research and Splicing
- Genetic Neurodegenerative Diseases
- Autophagy in Disease and Therapy
- Drug Transport and Resistance Mechanisms
- Computational Drug Discovery Methods
- HER2/EGFR in Cancer Research
- Cell Image Analysis Techniques
- Hematopoietic Stem Cell Transplantation
- CAR-T cell therapy research
- Bone and Joint Diseases
- Cancer Mechanisms and Therapy
Massachusetts Institute of Technology
2019-2025
Broad Institute
2019-2024
Harvard University
2019-2021
Dana-Farber Cancer Institute
2021
Brigham and Women's Hospital
2019
Bowdoin College
2016
University of Chicago
1999
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...
Abstract Chronic obstructive pulmonary disease (COPD) is associated with age and smoking, but other determinants of the are incompletely understood. Clonal hematopoiesis indeterminate potential (CHIP) a common, age-related state in which somatic mutations clonal blood populations induce aberrant inflammatory responses. Patients CHIP have an elevated risk for cardiovascular disease, association COPD remains unclear. We analyzed whole-genome sequencing whole-exome data to detect 48 835...
Multiple myeloma (MM) is a plasma-cell neoplasm that treated with high-dose chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. The presence of somatic mutations in the peripheral blood termed clonal hematopoiesis indeterminate potential (CHIP) associated adverse outcomes. Targeted sequencing product from 629 MM patients by ASCT at Dana-Farber Cancer Institute (2003-2011) detects CHIP 136/629 (21.6%). most commonly mutated genes are...
Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER)-positive (ER+) breast cancer. Cyclin-dependent kinase 7 (CDK7) candidate target endocrine-resistant ER+ cancer models selective CDK7 (CDK7i) are development for the treatment of Nonetheless, precise mechanisms responsible activity CDK7i remain elusive. Herein, we sought unravel these mechanisms.
Immune evasion is a hallmark of cancer and central mechanism underlying acquired resistance to immune therapy. In allogeneic hematopoietic cell transplantation (alloHCT), late relapses can arise after prolonged alloreactive T-cell control, but the molecular mechanisms escape remain unclear. To identify evasion, we performed genetic analysis serial samples from 25 patients with myeloid malignancies who relapsed ≥1 year alloHCT. Using targeted sequencing microarray determine HLA...
Abstract Genomic screens and GWAS are powerful tools for identifying disease-modifying genes, but it is often challenging to understand the pathways by which these genes function. Here, we take an integrated approach that combines network analysis imaging-based pooled genetic perturbation study examine modifiers of Huntington’s disease (HD). The computational highlighted several in a subnetwork enriched neuronal development morphology. To test functional roles developed experimental pipeline...
Huntington's Disease (HD) is caused by a CAG repeat expansion in the gene encoding Huntingtin (HTT ) . While normal HTT function appears impacted mutation, specific pathways unique to versus loss of are unclear. To understand impact expansion, we evaluated biological signatures knockout ( KO) those that occur from applying multi-omics, live cell imaging, survival analysis and novel feature-based pipeline study cortical neurons (eCNs) derived an isogenic human embryonic stem series (RUES2)....
Abstract Missense mutants of p53 - such as the frequent hotspot variant R248Q exert a dominant-negative effect (DNE) on wildtype (WT) in cancer cells with monoallelic TP53 mutations. However, precise functional and molecular mechanisms DNE have remained elusive due to lack appropriate model systems. Here, we developed variety systems, including CRISPR-edited human isogenic cell lines transcriptional reporter lines, targeted protein degradation assays that were combined analyses functionally...
Clonal hematopoiesis results from somatic mutations in cancer driver genes hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis sequencing data 84,683 persons and identified common the 5-methylcytosine reader,
The majority of JAK2 V617F -negative myeloproliferative neoplasms (MPNs) have disease-initiating frameshift mutations in calreticulin ( CALR ), resulting a common carboxyl-terminal mutant fragment (CALR MUT representing an attractive source neoantigens for cancer vaccines. However, studies shown that -specific T cells are rare patients with MPN unknown reasons. We examined class I major histocompatibility complex (MHC-I) allele frequencies from two independent cohorts. observed MHC-I alleles...
Abstract Clonal hematopoiesis (CH) at time of autologous stem cell transplant (ASCT) has been shown to be associated with decreased overall survival (OS) and progression-free (PFS) in patients multiple myeloma not receiving immunomodulatory drugs (IMiD). However, the significance CH newly diagnosed patients, including ineligible its effect on clonal evolution during therapy era novel agents, well studied. Using our new algorithm differentiate tumor germline mutations from CH, we detected...
Missense mutations in the gene encoding microtubule-associated protein TAU (current and approved symbol is MAPT) cause autosomal dominant forms of frontotemporal dementia. Multiple models dementia based on transgenic expression human
ABSTRACT Age is the dominant risk factor for most chronic human diseases; yet mechanisms by which aging confers this are largely unknown. 1 Recently, age-related acquisition of somatic mutations in regenerating hematopoietic stem cell populations was associated with both hematologic cancer incidence 2–4 and coronary heart disease prevalence. 5 Somatic leukemogenic potential may confer selective cellular advantages leading to clonal expansion, a phenomenon termed ‘Clonal Hematopoiesis...
Traditionally population genetics precludes the use of same genetic individual more than once in Hardy-Weinberg (HW) based calculations due to model's explicit assumptions. However, when applied clonal plant populations this can be difficult do, and some circumstances, it may ecologically informative ramet as data unit. In fact, ecologists have varied definition from a strict adherence single point per genotype inclusive approach one ramet. With advent molecular tools, list facultatively...
The gene encoding the serotonin 5-HT(7) receptor (HTR7) has been considered as a candidate locus in several neuropsychiatric disorders, based on pharmacological evidence and ligand-binding studies. After determining over 3 kb of previously unpublished sequence from introns 1 2 HTR7, single base (C/T) polymorphism second intron HTR7 was found. Allele-specific PCR used to genotype marker 53 trios consisting subjects with autistic disorder both parents. Using transmission disequilibrium test...
Abstract Aβ peptides derived from the amyloid precursor protein (APP) have been strongly implicated in pathogenesis of Alzheimer’s disease. However, normal function APP and importance that role neurodegenerative disease is less clear. We recover Drosophila ortholog APP, Appl, an unbiased forward genetic screen for neurodegeneration mutants. perform comprehensive single cell transcriptional proteomic studies Appl mutant flies to investigate aging brain. find unexpected control multiple...
Abstract Despite years of intense investigation, the mechanisms underlying neuronal death in Alzheimer’s disease, most common neurodegenerative disorder, remain incompletely understood. To define relevant pathways, we integrated results an unbiased, genome-scale forward genetic screen for age-associated neurodegeneration Drosophila with human and disease-associated multi-omics. We measured proteomics, phosphoproteomics, metabolomics models disease identified variants that modify expression...
Abstract Missense mutations in the gene encoding microtubule-associated protein tau cause autosomal dominant forms of frontotemporal dementia. Multiple models dementia based on transgenic expression human experimental model organisms, including Drosophila , have been described. These replicate key features disease, but do not faithfully recreate genetic context disorder. Here we use CRISPR-Cas mediated editing to caused by P301L mutation creating orthologous mutation, P251L, endogenous gene....
<p>Focal CNVs in PDX1526-Mut and PDX1415-WT enriched transcription pathways between the two PDX models.</p>
<p>MYC transcription is impaired by CDK7 inhibition.</p>
<p>On-target effect of SY-1365 and modulation WT/DOX-Y537S mutant MCF7 cells gene expression after treatment over time.</p>
<p>Effect of samuraciclib on PalboS and PalboR T47D cells.</p>