30 results found
May P, Reid A, Robinson M, et al., 2023, FISH-negative BCR::ABL1-positive e19a2 chronic myeloid leukaemia: the most cryptic of insertions, BMC Medical Genomics, Vol: 16, Pages: 1-6, ISSN: 1755-8794
Background:Chronic myeloid leukaemia (CML) is one of the most well characterised human malignancies. Most patients have a cytogenetically visible translocation between chromosomes 9 and 22 which generates the pathognomonic BCR::ABL1 fusion gene. The derivative chromosome 22 (‘Philadelphia’ or Ph chromosome) usually harbours the fusion gene encoding a constitutively active ABL1 kinase domain. A small subset of patients have no detectable translocation. Historically, these ‘Philadelphia chromosome negative’ patients caused diagnostic confusion between CML and other myeloproliferative neoplasms; it is now well established that the BCR::ABL1 fusion gene can be generated via submicroscopic intrachromosomal insertion of ABL1 sequence into BCR, or, more rarely, of BCR into ABL1. The fusion genes arising from cryptic insertions are not detectable via G-banded chromosome analysis [karyotype] but can nevertheless always be detected using fluorescence in situ hybridisation (FISH) and/or qualitative reverse transcriptase PCR.Case presentation:A 43-year-old female presented with suspected CML in 2007; however, contemporaneous gold standard laboratory investigations, G-banded chromosome analysis and FISH, were both negative. The reverse transcriptase quantitative PCR (RT-qPCR) assay available at the time, which was capable of detecting the common BCR::ABL1 transcripts (e13a2/e14a2), was also negative. Upon review in 2009, the newly recommended reverse transcriptase multiplex PCR (capable of detecting all BCR::ABL1 transcripts including the atypical ones) subsequently detected an e19a2 fusion. The patient then responded to tyrosine kinase inhibitor therapy. In contrast, FISH studies of both samples with three commercially available probes remained consistently negative.Retrospective whole genome sequencing, undertaken as part of the 100,000 Genomes Project, has now revealed that the patient’s BCR::ABL1 fusion gene arose via a uniquely small insertion
Karadimitris A, 2021, Chromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma, Nature Communications, Vol: 12, Pages: 1-16, ISSN: 2041-1723
Multiple myeloma is a genetically heterogeneous cancer of the bone marrow plasma cells (PC). Distinct myeloma transcriptome profiles are primarily driven by myelomainitiating events (MIE) and converge into a mutually exclusive overexpression of the CCND1 and CCND2 oncogenes. Here, with reference to their normal counterparts, we find that myeloma PC enhanced chromatin accessibility combined with paired transcriptome profiling can classify MIE-defined genetic subgroups. Across and within different MM genetic subgroups, we ascribe regulation of genes and pathways critical for myeloma biology to unique or shared, developmentally activated or de novo formed candidate enhancers. Such enhancers co-opt recruitment of existing transcription factors, which although not transcriptionally deregulated per se, organise aberrant gene regulatory networks that help identify myeloma cell dependencies with prognostic impact. Finally, we identify and validate the critical super-enhancer that regulates ectopic expression of CCND2 in a subset of patients with MM and in chronic lymphocytic leukemia.
Rowan AG, May P, Badhan A, et al., 2021, Optimized protocol for a quantitative SARS-CoV-2 duplex RT-qPCR assay with internal human sample sufficiency control., Journal of Virological Methods, Vol: 294, Pages: 1-7, ISSN: 0166-0934
There is growing evidence that measurement of SARS-CoV-2 viral copy number can inform clinical and public health management of SARS-CoV-2 carriers and COVID-19 patients. Here we show that quantification of SARS-CoV-2 is feasible in a clinical setting, using a duplex RT-qPCR assay which targets both the E gene (Charité assay) and a human RNA transcript, RNase P (CDC assay) as an internal sample sufficiency control. Samples in which RNase P is not amplified indicate that sample degradation has occurred, PCR inhibitors are present, RNA extraction has failed or swabbing technique was insufficient. This important internal control reveals that 2.4% of nasopharyngeal swabs (15/618 samples) are inadequate for SARS-CoV-2 testing which, if not identified, could result in false negative results. We show that our assay is linear across at least 7 logs and is highly reproducible, enabling the conversion of Cq values to viral copy numbers using a standard curve. Furthermore, the SARS-CoV-2 copy number was independent of the RNase P copy number indicating that the per-swab viral copy number is not dependent on sampling- further allowing comparisons between samples. The ability to quantify SARS-CoV-2 viral copy number will provide an important opportunity for viral burden-guided public health and clinical decision making.
Spencer Chapman M, May PC, Olavarria E, et al., 2020, Three distinct hematological malignancies from a single germ cell tumor: a case report., Journal of Medical Case Reports, Vol: 14, ISSN: 1752-1947
BACKGROUND: The association between non seminomatous germ cell tumors (GCTs) and hematological malignancies of rare lineage has been described in the literature. In some of these cases there is evidence that the leukemia derives from a pluripotent primitive clone present in the original germ cell tumor. CASE PRESENTATION: We present a highly unusual case of a 23-year-old man of South Asian origin with a history of Klinefelter's syndrome who initially developed mediastinal non seminomatous GCT. Following treatment with surgery and standard chemotherapy he went on to develop three different hematological malignancies of distinct lineages in sequential fashion over a short time period. Despite treatment with multiple intensive chemotherapy regimens and a matched unrelated donor allogeneic stem cell transplant, he died 41 months after initial diagnosis of his GCT and 10 months after the first diagnosis of hematological malignancy. CONCLUSIONS: This is an extreme case that highlights the pluripotency and aggressiveness of these GCT-derived hematological malignancies, and the need for novel therapeutic approaches.
Silvestri G, Trotta R, Stramucci L, et al., 2020, Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on <i>MIR300</i> Antiproliferative and PP2A-Activating Functions, BLOOD CANCER DISCOVERY, Vol: 1, Pages: 48-67, ISSN: 2643-3230
Trasanidis N, Alvarez-Benayas J, Katsarou A, et al., 2019, Distinct Chromatin Accessibility Changes, Aberrant Transcription Factor Networks Combined with Novel Oncogenic Enhancers Characterise Myeloma-Initiating Genetic Events, 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Innes A, Wooley P, Szydlo R, et al., 2019, Complete remission with incomplete count recovery (CRi) prior to allogeneic HCT for acute myeloid leukaemia is associated with a high non-relapse mortality., Leukemia, Vol: 34, Pages: 667-670, ISSN: 1476-5551
Silvestri G, Stramucci L, Ellis J, et al., 2017, The Bone Marrow Niche Uses Mir-300 As a Biological Rheostat to Selectively Control Stem Cell-Driven Malignant Hematopoiesis and Innate Anti-Cancer Immunity, 59th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Boulianne B, Robinson ME, May PC, et al., 2017, Lineage-specific genes are prominent DNA damage hotspots during leukemic transformation of B-cell precursors, Cell Reports, Vol: 18, Pages: 1687-1698, ISSN: 2211-1247
In human leukemia, lineage-specific genes represent predominant targets of deletion, with lymphoid-specific genes frequently affected in lymphoid leukemia and myeloid-specific genes in myeloid leukemia. To investigate the basis of lineage-specific alterations, we analyzed global DNA damage in primary B-cell precursors expressing leukemia-inducing oncogenes by ChIP-Seq. We identified >1000 sensitive regions, of which B-lineage-specific genes constitute the most prominent targets. Identified hotspots at B-lineage genes relate to DNA-DSBs, affect genes that harbor genomic lesions in human leukemia, and associate with ectopic deletionin successfully transformed cells. We further show that mostidentified regions overlap with gene bodies of highly expressed genes, and that induction of a myeloidlineage phenotype in transformed B-cell precursors promotes de novoDNA damage atmyeloid loci. Hence, we demonstrate thatlineage-specific transcriptionpredisposeslineage-specificgenes in transformed B-cell precursorsto DNA damage, whichis likely to promote the frequent alteration oflineage-specific genes in human leukemia.
May PC, Khorashad JS, Alikian M, et al., 2016, The genetics of chronic myelogenous leukaemia, The Genetic Basis of Haematological Cancers, Editors: Reid, Tosi, Publisher: John Wiley & Sons, ISBN: 9781118528051
Written by a team of international experts, this book provides an authoritative overview and practical guide to the molecular biology and genetic basis of haematologic cancers including leukemia.
Sebire NJ, May PC, Kaur B, et al., 2016, Abnormal Villous Morphology Mimicking a Hydatidiform Mole Associated with Paternal Trisomy of Chromosomes 3,7,8 and Unipaternal Disomy of Chromosome 11., Diagnostic Pathology, Vol: 11, ISSN: 1746-1596
BackgroundPregnancies affected by non-molar chromosomal abnormality may sometimes demonstrate abnormal chorionic villous morphology that is similar to partial hydatidiform mole. Determination of the underlying aetiology may be difficult in such cases.Case PresentationThis report describes a case referred to the regional trophoblastic disease unit as a possible hydatidiform mole that demonstrated both villous dysmorphology and abnormal p57KIP2 expression. Molecular genotyping revealed that while most chromosomes in the villous tissue were diploid and biparental, chromosomes 3, 7 and 8 were trisomic with an additional paternally derived chromosome. In contrast chromosome 11 showed uniparental disomy of paternal origin a situation more usually associated with complete hydatidiform moles. This unusual case highlights that exceptions may occur to the general rules of both histological morphology and immunoprofile, and that these can be resolved by detailed molecular genetic investigations.ConclusionThe findings confirm that trisomic pregnancies may demonstrate morphological villous features similar to hydatidiform mole, and that loss of p57KIP2 expression occurs due to an absence of maternally transcribed genes on chromosome 11 and can therefore be independent of androgenetic complete hydatidiform mole.
Johnston AC, Naresh K, Barwick T, et al., 2015, Cutaneous presentation of an aggressive plasmablastic neoplasm indiscriminate between lymphoma and myeloma, ANNALS OF HEMATOLOGY, Vol: 94, Pages: 691-692, ISSN: 0939-5555
Neelakantan P, Rezvani K, May P, et al., 2014, Excellent outcome after repeated changes of tyrosine kinase inhibitor therapy for chronic myeloid leukaemia in complete cytogenetic response due to minor side effects, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 164, Pages: 608-610, ISSN: 0007-1048
Neviani P, Harb JG, Oaks JJ, et al., 2013, PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells, JOURNAL OF CLINICAL INVESTIGATION, Vol: 123, Pages: 4144-4157, ISSN: 0021-9738
Auner HW, Moody AM, Ward TH, et al., 2013, Combined Inhibition of p97 and the Proteasome Causes Lethal Disruption of the Secretory Apparatus in Multiple Myeloma Cells, PLOS One, Vol: 8, ISSN: 1932-6203
Inhibition of the proteasome is a widely used strategy for treating multiple myeloma that takes advantage of the heavy secretory load that multiple myeloma cells (MMCs) have to deal with. Resistance of MMCs to proteasome inhibition has been linked to incomplete disruption of proteasomal endoplasmic-reticulum (ER)-associated degradation (ERAD) and activation of non-proteasomal protein degradation pathways. The ATPase p97 (VCP/Cdc48) has key roles in mediating both ERAD and non-proteasomal protein degradation and can be targeted pharmacologically by small molecule inhibition. In this study, we compared the effects of p97 inhibition with Eeyarestatin 1 and DBeQ on the secretory apparatus of MMCs with the effects induced by the proteasome inhibitor bortezomib, and the effects caused by combined inhibition of p97 and the proteasome. We found that p97 inhibition elicits cellular responses that are different from those induced by proteasome inhibition, and that the responses differ considerably between MMC lines. Moreover, we found that dual inhibition of both p97 and the proteasome terminally disrupts ER configuration and intracellular protein metabolism in MMCs. Dual inhibition of p97 and the proteasome induced high levels of apoptosis in all of the MMC lines that we analysed, including bortezomib-adapted AMO-1 cells, and was also effective in killing primary MMCs. Only minor toxicity was observed in untransformed and non-secretory cells. Our observations highlight non-redundant roles of p97 and the proteasome in maintaining secretory homeostasis in MMCs and provide a preclinical conceptual framework for dual targeting of p97 and the proteasome as a potential new therapeutic strategy in multiple myeloma.
Deplano S, May PC, Pavlu J, 2013, Double minutes with <i>MYC</i> amplification in a patient with chronic myelomonocytic leukaemia transformed into acute myeloid leukaemia, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 162, Pages: 720-720, ISSN: 0007-1048
Neelakantan P, Gerrard G, Lucas C, et al., 2013, Combining BCR-ABL1 transcript levels at 3 and 6 months in chronic myeloid leukemia: implications for early intervention strategies, BLOOD, Vol: 121, Pages: 2739-2742, ISSN: 0006-4971
Ahmed SO, Deplano S, May PC, et al., 2013, Observation of auer rods in crushed cells helps in the diagnosis of acute promyelocytic leukemia, AMERICAN JOURNAL OF HEMATOLOGY, Vol: 88, Pages: 236-236, ISSN: 0361-8609
Chaidos A, Barnes CP, Cowan G, et al., 2013, Clinical drug resistance linked to interconvertible phenotypic and functional states of tumor-propagating cells in multiple myeloma, BLOOD, Vol: 121, Pages: 318-328, ISSN: 0006-4971
Innes A, May PC, Pavlu J, et al., 2012, Unexpected pancytopenia following treatment of acute lymphoblastic leukemia, AMERICAN JOURNAL OF HEMATOLOGY, Vol: 87, Pages: 412-412, ISSN: 0361-8609
Al-Shieban S, Liu C, Fishlock K, et al., 2012, Bone marrow trephine biopsy findings in acute promyelocytic leukemia., Am J Hematol, Vol: 87, Pages: 109-110
Abdalla S, May PC, Garimberti E, et al., 2011, Bone marrow trephine biopsy findings in myeloma with small-lymphoid cells and CCND1 translocation, AMERICAN JOURNAL OF HEMATOLOGY, Vol: 86, Pages: 1038-1038, ISSN: 0361-8609
Ahmad OS, Fishlock K, May P, et al., 2011, Peripheral blood and bone marrow findings in B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma., Am J Hematol
Schwarb H, May PC, Apperley J, et al., 2011, Bone marrow trephine biopsy findings in B acute lymphoblastic leukaemia of early precursor (Pro-B) subtype, AMERICAN JOURNAL OF HEMATOLOGY, Vol: 86, Pages: 195-196, ISSN: 0361-8609
Daghistani M, Marin D, Khorashad JS, et al., 2010, EVI-1 oncogene expression predicts survival in chronic-phase CML patients resistant to imatinib treated with second-generation tyrosine kinase inhibitors, BLOOD, Vol: 116, Pages: 6014-6017, ISSN: 0006-4971
Naresh KN, May PC, Reid AG, et al., 2010, T cell lymphoblastic leukaemia/lymphoma associated with a microenvironment of thymic asteroid B cells in the bone marrow, HISTOPATHOLOGY, Vol: 57, Pages: 549-554, ISSN: 0309-0167
Khorashad J, Hu M, Hopmeier D, et al., 2010, NAMPT, A MEDIATOR OF NORMAL GRANULOCYTIC DIFFERENTIATION, IS DOWN-REGULATED IN CHRONIC MYELOID LEUKAEMIA VIA CHROMATIN MODIFICATION, Publisher: FERRATA STORTI FOUNDATION, Pages: 49-50, ISSN: 0390-6078
Bazeos A, Marin D, Reid AG, et al., 2010, hOCT1 transcript levels and single nucleotide polymorphisms as predictive factors for response to imatinib in chronic myeloid leukemia, LEUKEMIA, Vol: 24, Pages: 1243-1245, ISSN: 0887-6924
May PC, Foot N, Dunn R, et al., 2010, Detection of cryptic and variant <i>IGH</i>-<i>MYC</i> rearrangements in high-grade non-Hodgkin's lymphoma by fluorescence <i>in situ</i> hybridization: implications for cytogenetic testing, CANCER GENETICS AND CYTOGENETICS, Vol: 198, Pages: 71-75, ISSN: 0165-4608
May P, Thomas H, Scott R, et al., 2007, Reduction of maternal lymphocytes in bloodstained amniotic fluid by centrifugation and subsequent QF-PCR anuploidy testing, British Human Genetics Conference, Publisher: B M J PUBLISHING GROUP, Pages: S107-S107, ISSN: 0022-2593
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