Jacqueline Boultwood

Jacqueline Boultwood
University of Oxford | OX · Nuffield Division of Clinical Laboratory Sciences

About

261
Publications
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Publications

Publications (261)
Article
Full-text available
Mutations of the splicing factor-encoding gene U2AF1 are frequent in the myelodysplastic syndromes (MDS), a myeloid malignancy, and other cancers. Patients with MDS suffer from peripheral blood cytopenias, including anemia, and an increasing percentage of bone marrow myeloblasts. We studied the impact of the common U2AF1$^{S34F}$ mutation on cellul...
Article
Mutations of the splicing factor-encoding gene U2AF1 are frequent in the myelodysplastic syndromes (MDS), a myeloid malignancy, and other cancers. Patients with MDS suffer from peripheral blood cytopenias, including anemia, and an increasing percentage of bone marrow myeloblasts. We studied the impact of the common U2AF1S34F mutation on cellular fu...
Article
Full-text available
Background: Deletion of chromosome 5q (del(5q)) is the most common karyotypic abnormality in myeloid neoplasms. Materials and methods: To define the pathogenic molecular features associated with del(5q), next-generation sequencing was applied to 133 patients with myeloid neoplasms (MDS; N = 69, MDS/MPN; N = 5, sAML; N = 29, pAML; N = 30) with de...
Article
Full-text available
A high proportion of patients with lower-risk del(5q) myelodysplastic syndromes (MDS) will respond to treatment with lenalidomide. Median duration of transfusion-independence is 2 years with some long-lasting responses, but almost 40% of patients progress to acute leukemia by 5 years after start of treatment. Mechanisms underlying disease progressi...
Article
Splicing factor gene mutations are the most frequent mutations found in patients with the myeloid malignancy myelodysplastic syndrome (MDS), suggesting that spliceosomal dysfunction plays a major role in disease pathogenesis. The aberrantly spliced target genes and deregulated cellular pathways associated with the commonly mutated splicing factor g...
Article
Background: The myelodysplastic syndromes (MDS) are senescence-dependent stem cell malignancies. Although germ line mutations in RUNX1, CEBPA, ETV6, or GATA2 may underlie familial cases, inherited genetic polymorphisms influencing MDS susceptibility has not been evaluated. We performed the first genome-wide association study (GWAS) to identify sing...
Article
Full-text available
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) suppress normal hematopoietic activity in part by enabling a pathogenic inflammatory milieu in the bone marrow. In this report, we show that elevation of angiopoietin-1 in myelodysplastic CD34+ stem-like cells is associated with higher risk disease and reduced overall survival in MDS...
Article
Full-text available
The splicing factor SF3B1 is the most frequently mutated gene in the myelodysplastic syndromes (MDS), and is strongly associated with the presence of ring sideroblasts (RS). We have performed a systematic analysis of cryptic splicing abnormalities from RNA-sequencing data on hematopoietic stem cells (HSCs) of SF3B1-mutant MDS cases with RS. Aberran...
Article
We tested the hypothesis, that proliferative activity of hematopoietic stem cells has impact on survival in newly diagnosed patients with myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML). RNA expression profiles of CD34(+) cells were analyzed in 125 MDS patients and compared to healthy controls. Prognostic impact on overall...
Article
Full-text available
Inherited gene variants play an important role in malignant diseases. The transcriptional repressor Growth factor independence 1 (GFI1) regulates hematopoietic stem cell (HSC) self-renewal and differentiation. A single nucleotide polymorphism of GFI1 (rs34631763) generates a protein with an asparagine (N) instead of a serine (S) at position 36 (GFI...
Article
Splicing is an essential cellular process which is carried out by the spliceosome in order to remove the introns and join the exons present in pre-mRNA transcripts. A variety of spliceosomal mutations have been recently identified in the myelodysplastic syndromes (MDS), a heterogeneous group of hematopoietic stem cell malignancies, revealing a new...
Article
Solid tumours contend with, and adapt to, a hostile micro-environment that includes limited availability of nutrient fuels and oxygen. The presence of hypoxia (O2 < 5%) stabilises the transcription factor Hif1 and results in numerous cellular adaptations including increased flux of glucose through glycolysis. Increasingly more sophisticated analysi...
Article
Full-text available
The 5q- syndrome is the most distinct of the myelodysplastic syndromes (MDS) and patients with this disorder have a deletion of chromosome 5q [del(5q)] as the sole karyotypic abnormality. Several genes mapping to the commonly deleted region of the 5q- syndrome have been implicated in disease pathogenesis in recent years. Haploinsufficiency of the r...
Article
Background Somatic mutations identified in patients with myelodysplastic syndromes (MDS) are associated with disease features and carry prognostic information independent of the International Prognostic Scoring System (IPSS) and the revised IPSS (IPSS-R). Risk models that include mutation information have been proposed, but not widely adopted. In p...
Article
Full-text available
Recurrent somatic mutations of the epigenetic modifier and tumor suppressor ASXL1 are common in myeloid malignancies, including chronic myeloid leukemia (CML), and are associated with poor clinical outcome. CRISPR/Cas9 has recently emerged as a powerful and versatile genome editing tool for genome engineering in various species. We have used the CR...
Article
Full-text available
Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Loss or deletion of chromosome 7 is commonly seen in MDS and leads to a poor prognosis. However, the identity of functionally relevant, dysplasia-causing, genes on 7q remains unclear. Dedicator of cytokinesis 4 (DOCK4) is a GTPase exchange factor, and its gene maps...
Data
Fig S1. Expression ratios for CSNK1A1 [n = 3 cases with del(5q)] and CCND1 [n = 3 cases with del(5q)] obtained from real‐time quantitative PCR (blue bars) and Affymetrix experiments (red bars).
Article
Genome editing technologies have advanced significantly over the past few years, providing a fast and effective tool to precisely manipulate the genome at specific locations. The three commonly used genome editing technologies are Zinc Finger Nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs), and the Clustered Regularly Int...
Article
Full-text available
The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndrome (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). We investigated the functional effects of SF3B1 disruption in myeloid cell lines: SF3B1 knockdown resulted in growth inhibition, cell cycle arrest and impaired erythroid di...
Article
Full-text available
Poor clinical outcome of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) has been attributed to failure of current chemotherapeutic regimens to target leukemic stem cells. We recently identified p21-activated kinase (PAK1) as a downstream effector molecule of H2.0-like homeobox (HLX), a gene functionally relevant for AML pathogenesi...
Article
Full-text available
Mutations of CSNK1A1, a gene mapping to the commonly deleted region of the 5q- syndrome, have been recently described in patients with del(5q) myelodysplastic syndromes (MDS). Haploinsufficiency of Csnk1a1 in mice has been shown to result in β-catenin activation and expansion of haematopoietic stem cells (HSC). We have screened a large cohort of 10...
Article
CRISPR/Cas is a microbial adaptive immune system that uses RNA-guided nucleases to cleave foreign genetic elements. The CRISPR/Cas9 method has been engineered from the type II prokaryotic CRISPR system and uses a single-guide RNA to target the Cas9 nuclease to a specific genomic sequence. Cas9 induces double-stranded DNA breaks which are repaired e...
Article
Full-text available
Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
Article
AML and MDS are associated with disease initiating stem cells that are not eliminated by conventional therapies. Novel therapeutic targets against pre-leukemic stem cells need to be identified for potentially curative strategies. We conducted parallel transcriptional analysis of highly fractionated stem and progenitor populations in MDS, AML and co...
Article
Recent studies have greatly illuminated the genomic landscape of the myelodysplastic syndromes (MDS), and the pace of discovery is accelerating. The most common mutations found in MDS occur in genes involved in RNA splicing (including SF3B1, SRSF2, U2AF1 and ZRSR2) and epigenetic modification (including TET2, ASXL1 and DNMT3A). The identification o...
Article
Full-text available
Cancer is a genetic disease, but two patients rarely have identical genotypes. Similarly, patients differ in their clinicopathological parameters, but how genotypic and phenotypic heterogeneity are interconnected is not well understood. Here we build statistical models to disentangle the effect of 12 recurrently mutated genes and 4 cytogenetic alte...
Article
Full-text available
Atypical Chronic Myeloid Leukemia (aCML) is a clonal disorder belonging to the Myeloproliferative/Myelodysplastic (MPN/MDS) group. The molecular lesions responsible for the onset of aCML remained unknown until 2013 when recurrent somatic mutations of SETBP1 were identified. However, the frequency of SETBP1 mutations in aCML does not exceed 25-30%,...
Conference Paper
Full-text available
Approximately 30-40% of patients with myelodysplastic syndromes (MDS) develop acute myeloid leukemia (AML). Several recurrent mutations have been identified in MDS using next-generation sequencing (NGS) technology and recent studies have greatly illuminated the molecular landscape of this disorder. However, the molecular events driving MDS progress...
Article
Full-text available
The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndromes (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). We investigated the functional effects of SF3B1 disruption in myeloid cell lines: SF3B1 knockdown resulted in growth inhibition, cell cycle arrest and impaired erythroid d...
Article
Full-text available
Despite the recent identification of recurrent SETBP1 mutations in atypical chronic myeloid leukemia (aCML), a complete description of the somatic lesions responsible for the onset of this disorder is still lacking. To find additional somatic abnormalities in aCML, we performed whole-exome sequencing on 15 aCML cases. In 2 cases (13.3%), we identif...
Article
Myelodysplastic syndromes (MDS) are hematologic malignancies characterized by hematopoietic stem cell dysfunction that leads to ineffective hematopoiesis and cytopenias. Even though a third of MDS cases transform to leukemia, most of the mortality in MDS is due to low blood counts that occur because of failure of hematopoiesis. Development of effec...
Article
Diamond-Blackfan anemia (DBA) is an inherited hypoplastic anemia characterized by impaired production of erythroid cells, and it is caused by inactivating mutations in ribosomal protein genes in more than half of all cases. A new study in human cells demonstrates that reduced translation of the transcription factor GATA1, as a consequence of riboso...
Article
Full-text available
The myelodysplastic syndromes (MDSs) include a spectrum of stem cell malignancies characterized by an increased risk of developing acute myeloid leukemia. Heterozygous loss of chromosome 5q (del[5q]) is the most common cytogenetic abnormality in MDS. DIAPH1 is localized to 5q31 and encodes one of the formin proteins, mDia1, which is involved in lin...
Article
Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which different cancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical r...
Article
Full-text available
Mutations of spliceosome components are common in myeloid neoplasms. One of the affected genes, PRPF8, encodes the most evolutionarily conserved spliceosomal protein. We identified either recurrent somatic PRPF8 mutations or hemizygous deletions in 15/447 and 24/450 cases, respectively. 50% of PRPF8 mutant and del(17p) cases were found in AML and c...
Article
Full-text available
Mutations within BRCA1 predispose carriers to a high risk of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through the assembly of multiple protein complexes involved in DNA repair, cell-cycle arrest, and transcriptional regulation. Here, we report the identification of a DNA damage-induced BRCA1 protein complex containi...
Article
Despite the established use of poly-chemotherapy, relapse continues to be the most common cause of death in AML and MDS and cure rates remain below 20%. AML/MDS arise following the accumulation of stepwise genetic and epigenetic changes in hematopoietic stem and progenitor cells (HSPC). Utilizing a novel strategy of parallel transcriptional analysi...
Article
Full-text available
Myelodysplastic syndromes (MDSs) are clonal disorders of the hematopoietic stem cell.¹ MDS represents an excellent model of leukemic transformation with ~30–40% of MDS patients developing acute myeloid leukemia (AML).¹ The molecular basis of leukemic transformation in MDS remains poorly understood and there is a compelling need to identify the spec...
Article
Full-text available
Stabilization of p53 in erythroid precursors in response to nucleosomal stress underlies the hypoplastic anemia in myelodysplastic syndromes (MDS) with chromosome 5q deletion [del(5q)]. We investigated whether cenersen, a clinically active 20-mer antisense oligonucleotide complementary to TP53 exon10, could suppress p53 expression and restore eryth...
Article
Accurate pre-mRNA splicing by the spliceosome is a fundamental cellular mechanism required to remove introns that are present in most protein-coding transcripts. The recent discovery of a variety of somatic spliceosomal mutations in the myelodysplastic syndromes (MDS), a heterogeneous group of myeloid malignancies, has revealed a new leukemogenic p...
Article
Full-text available
Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell s...