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1.  Targeted sequencing using a 47 gene multiple myeloma mutation panel (M3P) in -17p high risk disease 
British journal of haematology  2014;168(4):507-510.
Summary
We constructed a multiple myeloma (MM)-specific gene panel for targeted sequencing and investigated 72 untreated high-risk (del17p) MM patients. Mutations were identified in 78% of the patients. While the majority of studied genes were mutated at similar frequency to published literature, the prevalence of TP53 mutation was increased (28%) and no mutations were found in FAM46C. This study provides a comprehensive insight into the mutational landscape of del17p high-risk MM. Additionally, our work demonstrates the practical use of a customized sequencing panel, as an easy, cheap and fast approach to characterize the mutational profile of MM.
doi:10.1111/bjh.13171
PMCID: PMC4314325  PMID: 25302557
myeloma; cancer genetics; DNA mutation; DRUG resistance; genetic analysis
2.  [No title available] 
PMCID: PMC3904791  PMID: 24224649
3.  [No title available] 
PMCID: PMC3907701  PMID: 24245986
4.  [No title available] 
PMCID: PMC4060801  PMID: 24172081
5.  [No title available] 
PMCID: PMC4094128  PMID: 24224700
6.  Evolving Insights in the Pathogenesis and Therapy of Cutaneous T-cell lymphoma (Mycosis Fungoides and Sezary Syndrome) 
British journal of haematology  2011;155(2):150-166.
Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of malignancies derived from skin-homing T cells. The most common forms of CTCL are Mycosis Fungoides (MF) and Sezary Syndrome (SS). Accurate diagnosis remains a challenge due to the heterogeneity of presentation and the lack of highly characteristic immunophenotypical and genetic markers. Over the past decade molecular studies have improved our understanding of the biology of CTCL. The identification of gene expression differences between normal and malignant T-cells has led to promising new diagnostic and prognostic biomarkers that now need validation to be incorporated into clinical practice. These biomarkers may also provide insight into the mechanism of development of CTCL. Additionally, treatment options have expanded with the approval of new agents, such as histone deacetylase inhibitors. A better understanding of the cell biology, immunology and genetics underlying the development and progression of CTCL will allow the design of more rational treatment strategies for these malignancies. This review summarizes the clinical epidemiology, staging and natural history of MF and SS; discusses the immunopathogenesis of MF and the functional role of the malignant T-cells; and reviews the latest advances in MF and SS treatment.
doi:10.1111/j.1365-2141.2011.08852.x
PMCID: PMC4309373  PMID: 21883142
mycosis fungoides; Sezary syndrome; cutaneous T-cell lymphoma; cytokines; interleukin 15
7.  Glucocorticoid Resistance in a Multiple Myeloma Cell Line is Regulated by a Transcription Elongation Block in the Glucocorticoid Receptor Gene.1 
British journal of haematology  2008;144(6):856-864.
Summary
Glucocorticoid (GC) effects are mediated by the glucocorticoid receptor (GR). Several studies demonstrated that a lower number of receptors per cell was associated with poor GC response. The regulation of GR expression is complex; the levels of GR can be autologously regulated by its ligand and also by transcriptional, post-transcriptional and post-translational mechanisms. Using three human myeloma cell lines, that parallel the development of GC resistance, this work describes the mechanism involved in downregulation of GR expression. The decreased expression was neither due to mutations in the GR gene nor due to methylation of the promoters. A gradual decrease in GR transcripts was seen during the development of resistance, the level of expression of exon 1–2 RNA fragments remained the same in sensitive and resistant cell lines but ChIP assay demonstrated that RNA polymerase II, detectable throughout exon 2 to 3 in the sensitive cell, was undetectable on exon 3 in the resistant variant suggesting lower or no transcription at this site. These studies demonstrated that downregulation of GR mRNA in resistant cell line involves a block to transcriptional elongation within intron B of the GR gene. This block may represent an important element in the regulation of GR expression.
doi:10.1111/j.1365-2141.2008.07549.x
PMCID: PMC4303606  PMID: 19133980
Glucocorticoid Receptor; multiple myeloma; transcription elongation block; glucocorticoid resistance
8.  [No title available] 
PMCID: PMC4294220  PMID: 21332710
9.  [No title available] 
PMCID: PMC4290865  PMID: 22299775
10.  Krüppel-like Factor 4 activates HBG gene expression in primary erythroid cells 
British journal of haematology  2011;154(2):248-259.
Summary
The SP1/Krüppel-like Factor (SP1/KLF) family of transcription factors plays a role in diverse cellular processes, including proliferation, differentiation and control of gene transcription. The discovery of KLF1 (EKLF), a key regulator of HBB (β-globin) gene expression, expanded our understanding of the role of KLFs in erythropoiesis. In this study, we investigated a mechanism of HBG (γ-globin) regulation by KLF4. siRNA-mediated gene silencing and enforced expression of KLF4 in K562 cells substantiated the ability of KLF4 to positively regulate endogenous HBG gene transcription. The physiological significance of this finding was confirmed in primary erythroid cells, where KLF4 knockdown at day 11 significantly attenuated HBG mRNA levels and enforced expression at day 28 stimulated the silenced HBG genes. In vitro binding characterization using the γ-CACCC and β-CACCC probes demonstrated KLF4 preferentially binds the endogenous γ-CACCC, while CREB binding protein (CREBBP) binding was not selective. Co-immunoprecipitation studies confirmed protein-protein interaction between KLF4 and CREBBP. Furthermore, sequential chromatin immunoprecipitation assays showed co-localization of both factors in the γ-CACCC region. Subsequent luciferase reporter studies demonstrated that KLF4 trans-activated HBG promoter activity and that CREBBP enforced expression resulted in gene repression. Our data supports a model of antagonistic interaction of KLF4/CREBBP trans-factors in HBG regulation.
doi:10.1111/j.1365-2141.2011.08710.x
PMCID: PMC4288826  PMID: 21539536
Krüppel-like Factor 4; Krüppel-like Factor 12; CREB binding protein; HBG; erythroid cells
11.  Genetics on a WHIM 
British journal of haematology  2013;164(1):15-23.
We initially described the WHIM syndrome based on the combination of Warts, Hypogammaglobulinaemia, Infections and Myelokathexis (neutrophil retention in the bone marrow). Translational research led to the discovery that this rare immunodeficiency disease is caused by a heterozygous mutation in the CXCR4 gene. Recently, Plerixafor has been suggested as a treatment for WHIM syndrome due to its efficacy as a CXCR4 antagonist, closing the translational research loop. In this review, we will focus on the clinical manifestations, pathophysiology, diagnosis and possible therapies for this rare entity.
doi:10.1111/bjh.12574
PMCID: PMC3961560  PMID: 24111611
CXCR4; myelokathexis; neutropenia; plerixafor; WHIM
12.  IMATINIB 800MG DAILY INDUCES DEEPER MOLECULAR RESPONSES THAN IMATINIB 400MG DAILY: RESULTS OF SWOG S0325, AN INTERGROUP RANDOMIZED PHASE II TRIAL IN NEWLY DIAGNOSED CHRONIC PHASE CHRONIC MYELOID LEUKAEMIA 
British journal of haematology  2013;164(2):223-232.
The standard dose of imatinib for newly diagnosed patients with chronic phase chronic myeloid leukemia (CP-CML) is 400mg daily (IM400), but the optimal dose is unknown. This randomized phase II study compared the rates of molecular, haematologic and cytogenetic response to IM400 vs. imatinib 400mg twice daily (IM800) in 153 adult patients with CP-CML. Dose adjustments for toxicity were flexible to maximize retention on study. Molecular response (MR) at 12 months was deeper in the IM800 arm (4-log reduction of BCR-ABL1 mRNA: 25% vs. 10% of patients, P=0.038; 3-log reduction: 53% vs. 35%, P=0.049). During the first 12 months BCR-ABL1 levels in the IM800 arm were an average 2.9-fold lower than in the IM400 arm (P=0.010). Complete haematologic response was similar, but complete cytogenetic response was higher with IM800 (85% vs. 67%, P=0.040). Grade 3–4 toxicities were more common for IM800 (58% vs. 31%, P=0.0007), and were most commonly haematologic. Few patients have relapsed, progressed or died, but progression-free (P=0.048) and relapse-free (P=0.031) survival were superior for IM800. In newly diagnosed CP-CML patients, IM800 induced deeper molecular responses than IM400, with a trend for improved progression-free and overall survival, but was associated with more severe toxicity.
doi:10.1111/bjh.12618
PMCID: PMC4127316  PMID: 24383843
BCR-ABL; CML; imatinib
14.  Single Nucleotide Polymorphism Array Analysis of Bone Marrow Failure Patients Reveals Characteristic Patterns of Genetic Changes 
British journal of haematology  2013;164(1):73-82.
Summary
The bone marrow failure syndromes (BMFS) are a heterogeneous group of rare blood disorders characterized by inadequate haematopoiesis, clonal evolution, and increased risk of leukaemia. Single nucleotide polymorphism arrays (SNP-A) have been proposed as a tool for surveillance of clonal evolution in BMFS. To better understand the natural history of BMFS and to assess the clinical utility of SNP-A in these disorders, we analysed 124 SNP-A from a comprehensively characterized cohort of 91 patients at our BMFS centre. SNP-A were correlated with medical histories, haematopathology, cytogenetic and molecular data. To assess clonal evolution, longitudinal analysis of SNP-A was performed in 25 patients. We found that acquired copy number-neutral loss of heterozygosity (CN-LOH) was significantly more frequent in acquired aplastic anaemia (aAA) than in other BMFS (odds ratio 12.2, p<0.01). Homozygosity by descent was most common in congenital BMFS, frequently unmasking autosomal recessive mutations. Copy number variants (CNVs) were frequently polymorphic, and we identified CNVs enriched in neutropenia and aAA. Our results suggest that acquired CN-LOH is a general phenomenon in aAA that is probably mechanistically and prognostically distinct from typical CN-LOH of myeloid malignancies. Our analysis of clinical utility of SNP-A shows the highest yield of detecting new clonal haematopoiesis at diagnosis and at relapse.
doi:10.1111/bjh.12603
PMCID: PMC3986350  PMID: 24116929
bone marrow failure; aplastic anaemia; chromosomal rearrangements; clonal evolution; cytogenetic diagnosis
15.  Bone marrow stroma-mediated resistance to FLT3 inhibitors in FLT3-ITD AML is mediated by persistent activation of extracellular regulated kinase 
British journal of haematology  2013;164(1):61-72.
Summary
A consistent pattern of response has been observed when FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitors (TKIs) have been used as monotherapy to treat patients with relapsed or refractory FLT3- internal tandem duplication (ITD) acute myeloid leukaemia (AML). Circulating blasts are cleared from the peripheral blood, while bone marrow blasts are either unaffected or are cleared from the marrow at a much slower rate. We used an in vitro model of FLT3-ITD AML blasts co-cultured with normal human bone marrow stromal cells to investigate the basis for this dichotomous response pattern to FLT3 inhibitors. We have found that in blasts on stroma, potent FLT3 inhibition predominantly results in cell cycle arrest rather than apoptosis. The anti-apoptotic effect is mediated through a combination of direct cell-cell contact and soluble factors. The addition of exogenous FLT3 ligand (FL) augments the protection, primarily by shifting the 50% inhibitory concentration for FLT3 inhibition upwards. Cytokine-activated extracellular regulated kinase (ERK), rather than STAT5, appears to be the most important downstream signalling protein mediating the protective effect, and inhibition of MEK significantly abrogates stromal-mediated resistance. These findings explain the phenomenon of peripheral blood versus bone marrow blast responses and suggest that the combination of potent FLT3 inhibition and MEK inhibition is a promising strategy for the treatment of FLT3-ITD AML.
doi:10.1111/bjh.12599
PMCID: PMC4076672  PMID: 24116827
acute myeloid leukaemia; FLT3-ITD; quizartinib; bone marrow stroma; extracellular regulated kinase
16.  Pro-apoptotic TP53 homolog TAp63 is repressed via epigenetic silencing and B-cell receptor signalling in chronic lymphocytic leukaemia 
British journal of haematology  2013;163(5):590-602.
Summary
Chronic lymphocytic leukaemia (CLL) is an accumulative disorder marked by deficient apoptosis. The TP53 homolog TAp63 promotes apoptosis and chemosensitivity in solid tumours and its deregulation may contribute to CLL cell survival. We found that TAp63α was the most prevalent TP63 isoform in CLL. Compared to healthy B cells, TAp63 mRNA was repressed in 55.7% of CLL samples. TP63 promoter methylation was high in CLL and inversely correlated with TP63 protein expression in B-cell lymphoma cell lines. siRNA-mediated knockdown of TP63 resulted in partial protection from spontaneous apoptosis accompanied by reductions in PMAIP1 (NOXA), BBC3 (PUMA), and BAX mRNA in CLL cells and increased proliferation of Raji lymphoma cells. TAp63 mRNA levels were higher in CLL with unmutated IGHV. B cell receptor (BCR) engagement led to repression of TP63 mRNA expression in malignant B cells, while pharmacological inhibition of BCR signalling prevented TP63 downregulation. MIR21, known to target TAp63, correlated inversely with TAp63 expression in CLL, and BCR-mediated downregulation of TP63 was accompanied by MIR21 upregulation in most CLL samples. Our data illustrate the pro-apoptotic function of TP63, provide insights into the mechanisms of BCR-targeting agents, and establish a rationale for designing novel approaches to induce TP63 in CLL and B-cell lymphoma.
doi:10.1111/bjh.12580
PMCID: PMC3939033  PMID: 24117128
TP63; B-cell receptor; chronic lymphocytic leukaemia; methylation
17.  Parasite maturation and host serum iron influence the labile iron pool of erythrocyte stage Plasmodium falciparum 
British journal of haematology  2013;161(2):262-269.
Summary
Iron is a critical and tightly regulated nutrient for both the malaria parasite and its human host. The importance of the relationship between host iron and the parasite has been underscored recently by studies showing that host iron supplementation may increase the risk of falciparum malaria. It is unclear what host iron sources the parasite is able to access. We developed a flow cytometry-based method for measuring the labile iron pool (LIP) of parasitized erythrocytes using the nucleic acid dye STYO 61 and the iron sensitive dye, calcein acetoxymethyl ester (CA-AM). This new approach enabled us to measure the LIP of P. falciparum through the course of its erythrocytic life cycle and in response to the addition of host serum iron sources. We found that the LIP increases as the malaria parasite develops from early ring to late schizont stage, and that the addition of either transferrin or ferric citrate to culture media increases the LIP of trophozoites. Our method for detecting the LIP within malaria parasitized RBCs provides evidence that the parasite is able to access serum iron sources as part of the host vs. parasite arms race for iron.
doi:10.1111/bjh.12234
PMCID: PMC4249674  PMID: 23398516
Plasmodium falciparum; iron; labile iron pool; malaria; calcein acetoxymethyl ester
18.  Renal dysfunction in patients with thalassaemia 
British journal of haematology  2011;153(1):111-117.
Summary
Little is known about the effects of thalassaemia on the kidney. Characterization of underlying renal function abnormalities in thalassaemia is timely because the newer iron chelator, deferasirox, can be nephrotoxic. We aimed to determine the prevalence and correlates of renal abnormalities in thalassaemia patients, treated before deferasirox was widely available, using 24-h collections of urine. We calculated creatinine clearance and urine calcium-to-creatinine ratio and measured urinary β2-microglobulin, albumin, and protein. We used multivariate modelling to identify clinical, therapeutic, and laboratory predictors of renal dysfunction. One-third of thalassaemia patients who were not regularly transfused had abnormally high creatinine clearance. Regular transfusions were associated with a decrease in clearance (P = 0·004). Almost one-third of patients with thalassaemia had hypercalciuria, and regular transfusions were associated with an increase in the frequency and degree of hypercalciuria (P < 0·0001). Albuminuria was found in over half of patients, but was not consistently associated with transfusion therapy. In summary, renal hyperfiltration, hypercalciuria, and albuminuria are common in thalassaemia. Higher transfusion intensity is associated with lower creatinine clearance but more frequent hypercalciuria. The transfusion effect needs to be better understood. Awareness of underlying renal dysfunction in thalassaemia can inform decisions now about the use and monitoring of iron chelation.
doi:10.1111/j.1365-2141.2010.08477.x
PMCID: PMC4250090  PMID: 21332704
thalassaemia; kidney; creatinine clearance; hyperfiltration; hypercalciuria; albuminuria; proteinuria; transfusion
19.  The transcription factor ATOH8 is regulated by erythropoietic activity and regulates HAMP transcription and cellular pSMAD1,5,8 levels 
British Journal of Haematology  2013;164(4):586-596.
Summary
ATOH8 has previously been shown to be an iron-regulated transcription factor, however its role in iron metabolism is not known. ATOH8 expression in HEK293 cells resulted in increased endogenous HAMP mRNA levels as well as HAMP promoter activity. Mutation of the E-box or SMAD response elements within the HAMP promoter significantly reduced the effects of ATOH8, indicating that ATOH8 activates HAMP transcription directly as well as through bone morphogenic protein (BMP) signalling. In support of the former, Chromatin immunoprecipitation assays provided evidence that ATOH8 binds to E-box regions within the HAMP promoter while the latter was supported by the finding that ATOH8 expression in HEK293 cells led to increased phosphorylated SMAD1,5,8 levels. Liver Atoh8 levels were reduced in mice under conditions associated with increased erythropoietic activity such as hypoxia, haemolytic anaemia, hypotransferrinaemia and erythropoietin treatment and increased by inhibitors of erythropoiesis. Hepatic Atoh8mRNA levels increased in mice treated with holo transferrin, suggesting that Atoh8 responds to changes in plasma iron. ATOH8 is therefore a novel transcriptional regulator of HAMP, which is responsive to changes in plasma iron and erythroid activity and could explain how changes in erythroid activity lead to regulation of HAMP.
doi:10.1111/bjh.12649
PMCID: PMC4232863  PMID: 24236640
ATOH8; HAMP; iron; erythropoiesis; pSMAD1,5,8
20.  Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN 
British Journal of Haematology  2013;164(1):811-821.
Summary
Cereblon (CRBN), the molecular target of lenalidomide and pomalidomide, is a substrate receptor of the cullin ring E3 ubiquitin ligase complex, CRL4CRBN. T cell co-stimulation by lenalidomide or pomalidomide is cereblon dependent: however, the CRL4CRBN substrates responsible for T cell co-stimulation have yet to be identified. Here we demonstrate that interaction of the transcription factors Ikaros (IKZF1, encoded by the IKZF1 gene) and Aiolos (IKZF3, encoded by the IKZF3 gene) with CRL4CRBN is induced by lenalidomide or pomalidomide. Each agent promotes Aiolos and Ikaros binding to CRL4CRBN with enhanced ubiquitination leading to cereblon-dependent proteosomal degradation in T lymphocytes. We confirm that Aiolos and Ikaros are transcriptional repressors of interleukin-2 expression. The findings link lenalidomide- or pomalidomide-induced degradation of these transcriptional suppressors to well documented T cell activation. Importantly, Aiolos could serve as a proximal pharmacodynamic marker for lenalidomide and pomalidomide, as healthy human subjects administered lenalidomide demonstrated Aiolos degradation in their peripheral T cells. In conclusion, we present a molecular model in which drug binding to cereblon results in the interaction of Ikaros and Aiolos to CRL4CRBN, leading to their ubiquitination, subsequent proteasomal degradation and T cell activation.
doi:10.1111/bjh.12708
PMCID: PMC4232904  PMID: 24328678
lenalidomide; pomalidomide; Cereblon; Ikaros; Aiolos
21.  Establishment and operation of a Good Manufacturing Practice-compliant allogeneic Epstein-Barr virus (EBV)-specific cytotoxic cell bank for the treatment of EBV-associated lymphoproliferative disease 
British Journal of Haematology  2014;167(3):402-410.
Epstein-Barr virus (EBV) is associated with several malignancies, including post-transplant lymphoproliferative disorder (PTLD). Conventional treatments for PTLD are often successful, but risk organ rejection and cause significant side effects. EBV-specific cytotoxic T lymphocytes (CTLs) generated in vitro from peripheral blood lymphocytes provide an alternative treatment modality with few side effects, but autologous CTLs are difficult to use in clinical practice. Here we report the establishment and operation of a bank of EBV-specific CTLs derived from 25 blood donors with human leucocyte antigen (HLA) types found at high frequency in European populations. Since licensure, there have been enquiries about 37 patients, who shared a median of three class I and two class II HLA types with these donors. Cells have been infused into ten patients with lymphoproliferative disease, eight of whom achieved complete remission. Neither patient with refractory disease was matched for HLA class II. Both cases of EBV-associated non-haematopoietic sarcoma receiving cells failed to achieve complete remission. Thirteen patients died before any cells could be issued, emphasizing that the bank should be contacted before patients become pre-terminal. Thus, this third party donor-derived EBV-specific CTL cell bank can supply most patients with appropriately matched cells and most recipients have good outcomes.
doi:10.1111/bjh.13051
PMCID: PMC4232001  PMID: 25066775
cell therapy; Epstein-Barr virus; cytotoxicity; lymphoproliferative disease
22.  Pre-Diagnosis Cigarette Smoking and Overall Survival in Non-Hodgkin Lymphoma 
British journal of haematology  2013;163(3):352-356.
We examined whether smoking prior to non-Hodgkin lymphoma (NHL) diagnosis was associated with overall survival (OS) and conducted a meta-analysis to assess the evidence relating pre-diagnosis cigarette smoking with OS. Among 523 NHL patients, worse OS was suggested for greater pre-diagnostic smoking habits when compared to never smokers. In the meta-analysis (n=5 patient populations), inferior OS was observed for greater number of cigarettes smoked per day, years of cigarette smoking, and pack-years of cigarette smoking. The inferior survival was more pronounced for follicular than for diffuse large B-cell lymphoma. Pre-diagnosis cigarette smoking may adversely impact the survival of NHL patients.
doi:10.1111/bjh.12512
PMCID: PMC3797194  PMID: 23909494
cigarettes; smoking; non-Hodgkin lymphoma; pooled analysis; meta-analysis
23.  Rasburicase in the prevention of laboratory/clinical tumour lysis syndrome in children with advanced mature B-NHL: A Children’s Oncology Group Report 
British journal of haematology  2013;163(3):10.1111/bjh.12542.
Summary
Laboratory (LTLS) and clinical (CTLS) tumour lysis syndrome (TLS) are frequent complications in newly diagnosed children with advanced mature B cell non-Hodgkin lymphoma (B-NHL). Rasburicase, compared to allopurinol, results in more rapid reduction of uric acid in paediatric patients at risk for TLS. However, the safety and efficacy of rasburicase for the treatment or or prevention of TLS has not been prospectively evaluated. Children with newly diagnosed stage III–IV, bone marrow+ and/or central nervous system+ mature B-NHL received hydration and rasburicase prior to cytoreductive therapy. Rasburicase was safe and well-tolerated and there were no grade III–IV toxicities probably or directly related to rasburicase. Patients with an initial lactate dehydrogenase ≥2x upper limit of normal had a significantly elevated uric acid level (P=0.005), increased incidence of TLS (p-0.005) and lower glomerular filtration rate (GFR; p<0.001). Following rasburicase, there was only a 9% and 5% incidence of LTLS and CTLS, respectively. Furthermore, there was a significant improvement in estimated GFR from Day 0 to Day 7 following rasburicase (p=0.0007) and only 1.3% of patients required new onset renal assisted support after rasburicase administration. A TLS strategy incorporating rasburicase prior to cytoreductive chemotherapy proved safe and effective in preventing new onset renal failure and was associated with a significant improvement in GFR.
doi:10.1111/bjh.12542
PMCID: PMC3835461  PMID: 24032600
Rasburicase; Tumour lysis syndrome; Burkitt lymphoma; Diffuse large B-cell lymphoma; Paediatric
24.  Patients with chronic lymphocytic leukaemia and clonal deletion of both 17p13.1 and 11q22.3 have a very poor prognosis 
British journal of haematology  2013;163(3):326-333.
Summary
Detection of a 17p13.1 deletion (loss of TP53) or 11q22.3 deletion (loss of ATM), by fluorescence in situ hybridization (FISH), in chronic lymphocytic leukaemia (CLL) patients is associated with a poorer prognosis. Because TP53 and ATM are integral to the TP53 pathway, we hypothesized that 17p13.1- (17p-) and 11q22.3- (11q-) occurring in the same cell (clonal 17p-/11q-) would confer a worse prognosis than either 17p- or 11q-. We studied 2184 CLL patients with FISH (1995–2012) for the first occurrence of 17p-, 11q-, or clonal 17p-/11q-. Twenty (1%) patients had clonal 17p-/11q-, 158 (7%) had 17p- (including 4 with 17p- and 11q- in separate clones), 247 (11%) had 11q-, and 1759 (81%) had neither 17p- nor 11q-. Eleven of 15 (73%) tested patients with clonal 17p-/11q- had dysfunctional TP53 mutations. Overall survival for clonal 17p-/11q- was significantly shorter (1.9 years) than 17p- (3.1 years, p = 0.04), 11q- (4.8 years, p = <0.0001), or neither 17p- nor 11q- (9.3 years, p = <0.0001). Clonal 17p-/11q- thus conferred significantly worse prognosis, suggesting that loss of at least one copy of both TP53 and ATM causes more aggressive disease. Use of an ATM/TP53 combination FISH probe set could identify these very-high risk patients.
doi:10.1111/bjh.12534
PMCID: PMC3907074  PMID: 24032430
Chronic lymphocytic leukaemia; prognostic factors; fluorescencein situ hybridization (FISH); TP53; ATM
25.  Identification of HLA-A*0201-Restricted Cytotoxic T Lymphocyte Epitopes Derived from HLA-DOβ as a Novel Target for Multiple Myeloma 
British journal of haematology  2013;163(3):343-351.
Summary
Despite the recent development of effective therapeutic agents against multiple myeloma (MM), new therapeutic approaches, including immunotherapies, remain to be developed. Here we identified novel human leucocyte antigen (HLA)-A*0201 (HLAA2)-restricted cytotoxic T lymphocyte (CTL) epitopes from a B cell specific molecule HLA-DOβ (DOB) as a potential target for MM. By DNA microarray analysis, the HLADOB expression in MM cells was significantly higher than that in normal plasma cells. Twenty-five peptides were predicted to bind to HLA-A2 from the amino acid sequence of HLA-DOB. When screened for the immunogenicity in HLA-A2-transgenic mice immunized with HLA-DOB cDNA, 4 peptides were substantially immunogenic. By mass spectrometry analysis of peptides eluted from HLA-A2-immunoprecipitates of MM cell lines, only two epitopes, HLA-DOB232-240 (FLLGLIFLL) and HLA-DOB185-193 (VMLEMTPEL), were confirmed for their physical presence on cell surface. When healthy donor blood was repeatedly stimulated in vitro with these two peptides and assessed by antigen-specific γ-interferon secretion, HLA-DOB232-240 was more immunogenic than HLA-DOB185-193. Additionally, the HLA-DOB232-240-specific CTLs, but not the HLA-DOB185-193-specific CTLs, displayed an major histocompatibility complex class I-restricted reactivity against MM cell lines expressing both HLA-A2 and HLA-DOB. Taken together, based on the physical presence on tumour cell surface and high immunogenicity, HLA-DOB232-240 might be useful for developing a novel immunotherapy against MM.
doi:10.1111/bjh.12544
PMCID: PMC4137325  PMID: 24032635
multiple myeloma; HLA-DOβ; cytotoxic T lymphocyte; T cell epitope; DNA microarray

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