29 research outputs found
James Collord Folder
No full text7 pages of family history documents containing and related to Marjorie Grace McRae Collord; James Elton Collord; William Ramsey; Kelly Tarter - including: photos; Wedding; Index; Accident; obi
Collord, Grace M. (Birth, 1877-09-03)
No full textAddress: Eastern Ave.5174/Pg 187/1877/Twin/F W/U.S./U.S./R. F. Carver, MD.Original record filed in drawer labeled 'COHEN-CONDO'
Recurrent histone mutations in T-cell acute lymphoblastic leukaemia.
No full textMutations affecting key modifiable histone type 3 (H3; Supplementary Table 1) residues are frequent oncogenic events in certain solid tumours (Feinberg, et al 2016), and have also recently been implicated in a subset of acute myeloid leukaemia (AML)(Lehnertz, et al 2017). Here, we systematically reviewed the somatic mutations in >20,000 cancer specimens to identify tumours harbouring H3 mutations. In a subset of T-cell acute lymphoblastic leukaemia (T-ALL) we identified non-methionine mutations of the key modifiable H3 residues, lysine (K) 27 and 36
Abstract 1158: Modulation of splicing by inhibiting the kinase SRPK1 as a novel therapeutic strategy in myeloid leukemia
No full textAbstract
Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis, for which the therapeutic landscape has changed little for decades. Aberrant mRNA splicing plays a key role in cancer development and genes coding for several of the major components of the spliceosome are targeted by somatic mutations in numerous cancers including myelodysplastic syndromes and AML. Recently, myeloid neoplasms bearing spliceosome gene mutations were shown to be preferentially susceptible to pharmacological disruption of the spliceosome. Here we report that targeting the spliceosome can also be an effective therapeutic strategy in other types of AML.
Recently, we generated a comprehensive catalogue of genetic vulnerabilities in AML using CRISPR-Cas9 genome-wide recessive screens and reported several novel intuitive and non-intuitive therapeutic candidates. Amongst these we identify SRPK1, the gene coding for a serine-threonine kinase that phosphorylates the major spliceosome protein SRSF1. Here, we demonstrate that targeted genetic disruption of SRPK1 in AML driven by MLL-fusion genes, led to differentiation and apoptosis. Additionally, mice transplanted with human AML cell lines carrying the MLL-AF9 fusion gene, namely MOLM-13 and THP-1, presented a significant prolongation of survival when SRPK1 was genetically disrupted by CRISPR-Cas9 editing. Similar effects were seen with pharmacological inhibition of SRPK1 in vitro and in vivo. At the molecular level we show that genetic or pharmacological inhibition of SRPK1 was associated with profound changes in the splicing of multiple genes involved in the MLL leukemogenic program in association with significant changes in enzymatic modifications of core histone tails.
We proceeded to perform a genome-wide CRISPR drop-out screen for sensitizers of MOLM13 cells to pharmacological inhibition of SRPK1 and identified, amongst other genes, BRD4 as a sensitizer. We go on to show that the BRD inhibitor iBET-151 synergizes with SRPK1 inhibition to kill MOLM-13 both in vitro and in vivo. Preliminary data indicates that SRPK1 inhibition has overlapping molecular effects to BRD inhibition. We are currently investigating the molecular bases of this observation.
Our work identifies SRPK1 as a novel therapeutic target in AML that can be used alone or in conjunctions with drugs targeting epigenetic modifications to improve their anti-leukemic effects.
Citation Format: Konstantinos Tzelepis, Etienne De Braekeleer, Michael Seiler, Isaia Barbieri, Sam Robson, Yu Hsuen Yang, Malgorzata Gozdecka, Monika Dudek, Grace Collord, Oliver M. Dovey, Emmanouil Metzakopian, Dimitrios Garyfallos, Jonathan L. Cooper, Silvia Buonamici, Hannes Ponstingl, Michael R. Stratton, Allan Bradley, Brian J. Huntly, Cristina Pina, Tony Kouzarides, Kosuke Yusa, George S. Vassiliou. Modulation of splicing by inhibiting the kinase SRPK1 as a novel therapeutic strategy in myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1158. doi:10.1158/1538-7445.AM2017-1158</jats:p
Targeting MEK in vemurafenib-resistant hairy cell leukemia.
No full textTo the editor:
Hairy cell leukemia (HCL) is a chronic, incurable B cell malignancy that presents with splenomegaly, bone marrow infiltration and cytopenias(1). Long remissions are typically achieved with purine analogues such as cladribine, but most cases will relapse and require further therapy. The discovery of the BRAF V600E mutation in almost all cases of HCL(2) has led to the widespread adoption of the BRAF inhibitor vemurafenib for treatment of patients relapsing after cladribine(3-5). Impressive responses are reported; however, relapse is inevitable(5, 6) and hematologists are now faced with a growing number of patients with vemurafenib-resistant HCL. The optimal management of these patients remains unclear
Clonal haematopoiesis is not prevalent in survivors of childhood cancer
No full textClonal haematopoiesis driven by leukaemia-associated somatic mutations is a common feature of ageing (Link & Walter, 2016). This phenomenon, termed clonal haematopoiesis of indeterminate potential (CHIP), is associated with an increased risk of haematological malignancies and all-cause mortality (Link & Walter, 2016). Recent empirical evidence and computational models suggest that mutation acquisition may not be the major rate-limiting factor in the emergence of CHIP (Altrock et al, 2015; McKerrell et al, 2015; Link & Walter, 2016; Young et al, 2016). Instead, clonal expansion of mutant haematopoietic stem cells (HSCs) probably reflects the interaction between the effects of driver mutations and selection pressures prevailing in the bone marrow microenvironment (Link & Walter, 2016). Notably, cytotoxic therapies have been shown to favour expansion of pre-malignant haematopoietic clones (Link & Walter, 2016). Furthermore, both adult and paediatric cancer patients treated with intensive chemoradiotherapy display an earlier onset of ageing-associated morbidities and an elevated risk of therapy-related myeloid neoplasms (t-MN) and other secondary malignancies (Rowland & Bellizzi, 2014). A recent study in adult cancer patients found that CHIP was more prevalent than in the general population and was strongly associated with t-MN and overall mortality (Gibson et al, 2017). Although CHIP is extremely rare in healthy young individuals, its prevalence and prognostic significance in paediatric cancer patients has not been studied. We therefore performed targeted deep sequencing of peripheral blood DNA from 84 childhood cancer survivors to search for subclonal mutations common in t-MN and adult clonal haematopoiesis. No individuals with somatic variants at these loci were identified. Whilst our findings could be explained by a rarity of driver mutations, the fact that human HSCs accrue somatic variants from the first decade of life (Welch et al, 2012) proposes the alternative possibility that such mutations may not confer clonal advantage in the young.This project was funded by the Wellcome Trust Sanger Institute (grant number WT098051). G.S.V. is funded by a Wellcome Trust Senior Fellowship in Clinical Science (WT095663MA). F.F. is funded by Compagnia di San Paolo Grant: “Le cellule staminali del sangue nei guariti di leucemia” Codice SIME 2013-0958 (codice ROL 4201). I.V is funded by the Spanish Ministerio de Economía y Competitividad, Programa Ramón y Cajal
Single-cell transcriptomics reveals a distinct developmental state of <em>KMT2A</em>-rearranged infant B-cell acute lymphoblastic leukemia
No full text\ua9 2022, The Author(s). KMT2A-rearranged infant ALL is an aggressive childhood leukemia with poor prognosis. Here, we investigated the developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia (B-ALL) using bulk messenger RNA (mRNA) meta-analysis and examination of single lymphoblast transcriptomes against a developing bone marrow reference. KMT2A-rearranged infant B-ALL was uniquely dominated by an early lymphocyte precursor (ELP) state, whereas less adverse NUTM1-rearranged infant ALL demonstrated signals of later developing B cells, in line with most other childhood B-ALLs. We compared infant lymphoblasts with ELP cells and revealed that the cancer harbored hybrid myeloid–lymphoid features, including nonphysiological antigen combinations potentially targetable to achieve cancer specificity. We validated surface coexpression of exemplar combinations by flow cytometry. Through analysis of shared mutations in separate leukemias from a child with infant KMT2A-rearranged B-ALL relapsing as AML, we established that KMT2A rearrangement occurred in very early development, before hematopoietic specification, emphasizing that cell of origin cannot be inferred from the transcriptional state
JAK2 V617F hematopoietic clones are present several years prior to MPN diagnosis and follow different expansion kinetics
No full textMcKerrell, Thomas et al.The JAK2 V617F mutation is the most common somatic mutation in the classical myeloproliferative neoplasms (MPNs), present in >95% of cases of polycythemia vera (PV) and ~50% of essential thrombocythemia (ET) and myelofibrosis (MF).1-4 It is usually the sole identifiable driver mutation in MPNs5 and was recently also identified as a driver of age-related clonal hemopoiesis in healthy individuals.6-9 In order to investigate the preclinical clonal evolution of MPNs, we identified 12 individuals with a JAK2 V617F mutant MPN, who 4.6 to 15.2 years previously (median 10.2 years) had also donated blood to register with the Cyprus Bone Marrow Donor Registry at the Karaiskakio FoundationThis work was supported by the Wellcome Trust Sanger Institute (WT098051). T. McKerrell is funded by a Wellcome Trust Clinician Scientist Fellowship (100678/Z/12/Z). G.S.V. is funded by a Wellcome Trust Senior Fellowship in Clinical Science (WT095663MA), and work in his laboratory is also funded by Cancer Research UK,
Bloodwise, the Kay Kendall Leukaemia Fund, and Celgene. I.V. is supported by the Spanish Ministerio de Economía y Competitividad, Programa Ramón y Cajal.Peer Reviewe
Clonal hematopoiesis and therapy-related myeloid neoplasms following neuroblastoma treatment.
No full textTherapy-related myeloid neoplasms (TMN) constitute one of the most challengingcomplications of cancer treatment.1 Whilst understanding of TMN pathogenesis remains fragmentary, genomic studies in adults have thus far refuted the notion that TMN simply result from cytotoxin-induced DNA damage.2–4 Analysis of the preclinical evolution of a limited number of adult TMN have retraced the majority of cases to clonal haematopoiesis (CH) that predates cytotoxic treatment and lacks the mutational footprint of genotoxic therapies.2–6 Balanced translocations,
generally attributed to treatment with topoisomerase II inhibitors, are implicated in a minority of TMN.1 TMN is a leading cause of premature death in childhood cancer survivors, and affects 7-11% of children treated for high-risk neuroblastoma and sarcoma.7,8 However, the origin of pediatric TMN remains unclear. Targeted sequencing of known cancer genes detects CH in ~4% of children following cytotoxic treatment,6,9 whereas CH is vanishingly rare in young individuals in the general population.10,11 Moreover, to our knowledge, no cases of childhood TMN have been retraced to pretreatment CH. In light of these observations, we asked whether a broader driver landscape had eluded targeted CH screens in pediatric cancer patients and/or whether therapy-induced mutagenesis may be an under-recognised catalyst of CH and TMN in this patient group
