A5079999812- Acute Myeloid Leukemia Research
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Cancer Genomics and Diagnostics
- Epigenetics and DNA Methylation
- Acute Lymphoblastic Leukemia research
- Hematopoietic Stem Cell Transplantation
- Chronic Myeloid Leukemia Treatments
- Pluripotent Stem Cells Research
- Chronic Lymphocytic Leukemia Research
- Immune Cell Function and Interaction
- Histone Deacetylase Inhibitors Research
- Blood disorders and treatments
- T-cell and B-cell Immunology
- CRISPR and Genetic Engineering
- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- Immunodeficiency and Autoimmune Disorders
- Telomeres, Telomerase, and Senescence
- Hemoglobinopathies and Related Disorders
- Genomics and Rare Diseases
- Lymphoma Diagnosis and Treatment
- Neutropenia and Cancer Infections
- Immunotherapy and Immune Responses
- Eosinophilic Disorders and Syndromes
- Erythrocyte Function and Pathophysiology
Dana-Farber Cancer Institute
2016-2025
Boston University
2025
Harvard University
2015-2023
Broad Institute
2019-2023
Brigham and Women's Hospital
2011-2019
Massachusetts Institute of Technology
2019
Dana-Farber/Harvard Cancer Center
2019
Dana-Farber Brigham Cancer Center
2015-2018
Seagen (Canada)
2017
Bristol-Myers Squibb (United States)
2017
The incidence of hematologic cancers increases with age. These are associated recurrent somatic mutations in specific genes. We hypothesized that such would be detectable the blood some persons who not known to have disorders.
Genetic mutations drive the pathogenesis of myelodysplastic syndrome (MDS) and are closely associated with clinical phenotype. Therefore, genetic may predict outcomes after allogeneic hematopoietic stem-cell transplantation.We performed targeted mutational analysis on samples obtained before transplantation from 1514 patients MDS who were enrolled in Center for International Blood Marrow Transplant Research Repository between 2005 2014. We evaluated association outcomes, including overall...
Abstract Although immature/transitional peripheral B cells may remain susceptible to selection pressures before full maturation, the nature and timing of these events unclear. We show that correlated expression surface (s) IgM (sIgM), CD23, AA4 defines three nonproliferative subpopulations cells. designate populations transitional (T) 1 (AA4+CD23−sIgMhigh), T2 (AA4+CD23+sIgMhigh), T3 (AA4+CD23+sIgMlow). Cells within all subsets are functionally immature as judged by their failure proliferate...
Purpose Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition characterized by somatic mutations in the blood otherwise healthy adults. We hypothesized that patients undergoing autologous stem-cell transplantation (ASCT) for lymphoma, CHIP at time ASCT would be associated with increased risk myelodysplastic syndrome and acute myeloid leukemia, collectively termed therapy-related neoplasm (TMN), other adverse outcomes. Methods performed whole-exome sequencing on...
Recurrently mutated genes in myelodysplastic syndrome (MDS) are pathogenic drivers and powerfully associated with clinical phenotype prognosis. Whether these types of mutations predict outcome after allogeneic hematopoietic stem-cell transplantation (HSCT) patients MDS is not known.We used massively parallel sequencing to examine tumor samples collected from 87 before HSCT for coding 40 recurrently genes.Mutations were identified 92% patients, most frequently the ASXL1 (29%), TP53 (21%),...
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...
Formation of mesoderm from the pluripotent epiblast depends upon canonical Wnt/beta-catenin signaling, although a precise molecular basis for this requirement has not been established. To develop robust model developmental transition, we examined role Wnt signaling during analogous stage embryonic stem cell differentiation. We show that kinetics ligand expression and pathway activity in vitro mirror those found vivo. Furthermore, inhibition endogenous abrogates functional competence...
Clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia undetermined significance (CCUS) are defined by somatic mutations in genes associated with myeloid neoplasms (MN) at a variant allele fraction (VAF) ≥ 0.02, the absence presence cytopenia, respectively. CHIP/CCUS is highly prevalent adults defining predictors MN risk would aid clinical management research.
Abstract Aging is associated with functional decline of hematopoietic stem cells (HSC) as well an increased risk myeloid malignancies. We performed integrative characterization epigenomic and transcriptomic changes, including single-cell RNA sequencing, during normal human aging. Lineage−CD34+CD38− [HSC-enriched (HSCe)] undergo age-associated epigenetic reprogramming consisting redistribution DNA methylation reductions in H3K27ac, H3K4me1, H3K4me3. This aged HSCe globally targets...
Abstract To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. define mechanistic basis clonal hematopoiesis in SDS, investigate somatic mutations acquired by patients SDS followed longitudinally. Here report multiple independent hematopoietic clones arise life, most commonly harboring heterozygous EIF6 or...
Clonal hematopoiesis (CH) can be transmitted from a donor to recipient during allogeneic hematopoietic cell transplantation. Exclusion of candidate donors with CH is controversial since its impact on outcomes and graft alloimmune function uncertain.
Background. Responses to conventional donor lymphocyte infusion for postallogeneic hematopoietic cell transplantation (HCT) relapse are typically poor. Natural killer (NK) cell–based therapy is a promising modality treat post-HCT relapse.
Abstract These studies characterize BLyS responsiveness and receptor expression among transitional mature peripheral B cells. The results show a maturation-associated increase in binding capacity that reflects differential patterns of the three receptors. Accordingly, administration enlarges only late (MB) cell compartments. Furthermore, bromodeoxyuridine labeling cycle analyses these effects are mediated through enhanced proportional survival cells traversing T2, T3, MB stages, rather than...