Alexander Silver

• PhD
• MD-PhD Candidate at Vanderbilt University

The age‐associated mutational state of clonal haematopoiesis (CH) is linked to multiple adverse health outcomes. As higher risk CH can lead to progressive neoplastic or vascular disease, there is interest in developing clinical trials to mitigate risk associated with CH. Given the high prevalence of CH, data from clinical trials could have broad pu...

Environmental exposures have been postulated to affect the pathogenesis of many human diseases including blood cancers and predisposition conditions such as clonal hematopoiesis (CH). There are few systematic studies that have determined the magnitude of CH in well-defined cohorts of environmental exposures. We conducted deep sequencing analysis of...

WD40 Repeat Domain 5 (WDR5) is a highly conserved nuclear protein that recruits MYC oncoprotein transcription factors to chromatin to stimulate ribosomal protein gene expression. WDR5 is tethered to chromatin via an arginine-binding cavity known as the "WIN" site. Multiple pharmacological inhibitors of the WDR5-interaction site of WDR5 (WINi) have...

CRISPR-Cas9 is a useful tool for inserting precise genetic alterations through homology-directed repair (HDR), although current methods rely on provision of an exogenous repair template. Here, we tested the possibility of repairing heterozygous single nucleotide variants (SNVs) using the cell’s own wild-type allele rather than an exogenous template...

Clonal hematopoiesis (CH) is an age-associated phenomenon leading to increased risk of both hematologic malignancy and non-malignant organ dysfunction. Increasingly available genetic testing has made incidental discovery of CH clinically common, yet evidence-based guidelines and effective management strategies to prevent adverse CH health outcomes...

Purpose Solid organ transplant recipients comprise a unique population of immunosuppressed patients with increased risk of malignancy, including hematologic neoplasms. Clonal hematopoiesis of indeterminate potential (CHIP) represents a known risk factor for hematologic malignancy and this study describes the prevalence and patterns of CHIP mutation...

Clonal hematopoiesis (CH) is an age-associated phenomenon that increases risk for hematologic malignancy and cardiovascular disease. CH is thought to enhance disease risk through inflammation in the peripheral blood1. Here, we profile peripheral blood gene expression in 66,968 single cells from a cohort of 17 CH patients and 7 controls. Using a nov...

Impairing the BET family coactivator BRD4 with small-molecule inhibitors (BETi) showed encouraging preclinical activity in treating acute myeloid leukemia (AML). However, dose-limiting toxicities and limited clinical activity dampened the enthusiasm for BETi as a single agent. BETi resistance in AML myeloblasts was found to correlate with maintaini...

Clonal hematopoiesis (CH) can be caused by either single gene mutations (eg point mutations in JAK2 causing CHIP) or mosaic chromosomal alterations (e.g., loss of heterozygosity at chromosome 9p). CH is associated with a significantly increased risk of hematologic malignancies. However, the absolute rate of transformation on an annualized basis is...

Introduction Clonal hematopoiesis (CH), the expansion of a clonal population of hematopoietic cells, is an age-associated phenomenon leading to increased risk of both hematologic malignancy and non-malignant organ dysfunction. There have been significant advances in our understanding of the underlying pathophysiology of CH in recent years. However,...

Clonal hematopoiesis (CH) is an age-associated phenomenon which is known to increase the risk for hematologic malignancy and cardiovascular disease. The most commonly mutated gene in CH is de novo DNA methyltransferase DNMT3A. R882H and R882C are the most common hotspot mutations in this gene, and these mutations are commonly grouped together in in...

Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related phenomenon that occurs when hematopoietic stem cells acquire mutations in a select set of genes commonly mutated in myeloid neoplasia which then expand clonally. Current sequencing assays to detect CHIP are not optimized for the detection of these variants and can be cos...

OBJECTIVES/GOALS: Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related condition that confers an increased risk of blood cancer, cardiovascular disease, and overall mortality. Larger proportions of blood cells with the CHIP mutation (clones) lead to worse outcomes. The goal of this study was to characterize CHIP clonal beh...

Clonal hematopoiesis of indeterminate potential (CHIP) is a common form of age-related somatic mosaicism that is associated with significant morbidity and mortality. CHIP mutations can be identified in peripheral blood samples sequenced using approaches that cover the whole genome, whole exome or targeted genetic regions; however, differentiating t...

Clonal hematopoiesis (CH) is an age-associated phenomenon that increases risk for hematologic malignancy and cardiovascular disease. CH is thought to enhance disease risk through inflammation in the peripheral blood ¹ . Here, we profile peripheral blood gene expression in 66,968 single cells from a cohort of 17 CH patients and 7 controls. Using a n...

Clonal hematopoiesis of indeterminate potential (CHIP) is a common form of age-related somatic mosaicism that is associated with significant morbidity and mortality. CHIP mutations can be identified in peripheral blood samples sequenced using approaches that cover the whole genome, whole exome or targeted genetic regions; however, differentiating t...

With age, acquired mutations can cause clonal expansion of hematopoietic stem cells (HSC). This clonal hematopoiesis of indeterminate potential (CHIP) leads to an increased predisposition to numerous diseases including blood cancer and cardiovascular disease. Here, we report multi-ancestry genome-wide association meta-analyses of CHIP among 323,112...

Treatment decisions in primary myelofibrosis (PMF) are guided by numerous prognostic systems. Patient specific comorbidities have influence on treatment related survival, and are considered in clinical contexts, but have not been routinely incorporated into current prognostic models. We hypothesized that patient specific comorbidities would inform...

The terrorist attacks on the World Trade Center (WTC) created an unprecedented environmental exposure to aerosolized dust, gases and potential carcinogens. Clonal hematopoiesis (CH) is defined as the acquisition of somatic mutations in blood cells and is associated with smoking and exposure to genotoxic stimuli. Here we show that deep targeted sequ...

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) has been linked to increased risk of cardiovascular disease, mediated in part through inflammation. Like CHIP, aortic stenosis (AS) has a strong association with aging and involves pathologic inflammation. A prior study found that AS patients with CHIP have worse outcomes (Mas-Pei...

Clonal haematopoiesis (CH) is a common, age-related expansion of blood cells with somatic mutations that is associated with an increased risk of haematological malignancies, cardiovascular disease and all-cause mortality. CH may be caused by point mutations in genes associated with myeloid neoplasms, chromosomal copy number changes and loss of hete...

Background:Treatment decisions in primary myelofibrosis (PMF) are guided by several prognostic systems based on disease-specific risk factors, including complete blood counts and cytogenetics. Patient specific comorbidities, e.g. non-hematopoietic organ dysfunction, are not incorporated into current prognostic models. Likewise, PMF risk stratificat...

Background:Patients with clonal hematopoiesis (CH) in the absence of WHO-classified myeloid disease are of special interest given their increased prevalence with age, predisposition to morbid cardiovascular complications, and amplified risk of overt hematologic malignancy. Pts are often stratified by normal peripheral blood counts into clonal hemat...

Background: Myelodysplastic syndromes (MDS) are clonal hematologic neoplasms stratified by risk by the international prognostic scoring system (IPSS) and IPSS-revised (IPSS-R) which measure risk by morphologic dysplasia, clinical cytopenias, blast count, and cytogenetic abnormalities. (PMID: 9058730, 22740453) The IPSS/IPSS-R do not consider clinic...

Clonal hematopoiesis is a common, age-related process in which a somatically mutated hematopoietic precursor gives rise to a genetically distinct subpopulation in the blood. This phenomenon has been observed in populations across the globe and, while virtually non-existent in children is estimated to affect > 10% of the 70-and-older age group. The...

Clonal hematopoiesis of indeterminate potential (CHIP) was recently identified as a major risk factor for development of both hematologic malignancies and atherosclerotic cardiovascular disease in humans. The most commonly mutated gene in CHIP, DNMT3A, is a de novo DNA methyltransferase. The second most commonly mutated gene is TET2, an enzyme whic...

Truncating mutations in the terminal exon of protein phosphatase Mg2+/Mn2+ 1D (PPM1D) have been identified in clonal hematopoiesis and myeloid neoplasms, with a striking enrichment in patients previously exposed to chemotherapy. In this study, we demonstrate that truncating PPM1D mutations confer a chemoresistance phenotype, resulting in the select...

Thrombosis is a major cause of morbidity and mortality in Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs), clonal disorders of hematopoiesis characterized by activated Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling. Neutrophil extracellular trap (NET) formation, a component of innate immuni...

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection (LRTI) in children from infancy up to early childhood. Recently, we demonstrated that RSV infection alters cellular small non-coding RNA (sncRNA) expression, most notably the tRNA-derived RNA fragments (tRFs). However, the functions of the tRFs in virus-host...

Background Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association betw...

This study is the first to evaluate the existence and quality of patient-related cancer rehabilitation content on the websites of National Cancer Institute (NCI)-Designated Cancer Centers. In 2016, a team of cancer rehabilitation physicians (physiatrists) conducted an analysis of the patient-related rehabilitation content on the websites of all NCI...

One of the adverse consequences of chemotherapy exposure is the development of therapy-related myeloid neoplasms (t-MNs). However, the cause and origin of most t-MNs are unknown, and the prognosis remains dismal. Novel work has shown that in addition to TP53, PPM1D is selectively mutated in 15% of therapy related MDS (Lindsley et al., ASH Abstract)...

Background: Philadelphia-negative myeloproliferative neoplasms (MPNs) are a group of clonal stem-cell disorders that are associated with an elevated risk for thrombosis. The reason for this association is incompletely understood. While elevated white blood cell (WBC) count is a risk factor for thrombosis in some models, the pathogenic pathways link...