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1.  Casein kinase 2 controls the survival of normal thymic and leukemic γδ T cells via promotion of AKT signaling 
Leukemia  2016;31(7):1603-1610.
The thymus is the major site for normal and leukemic T-cell development. The dissection of the molecular determinants of T-cell survival and differentiation is paramount for the manipulation of healthy or transformed T cells in cancer (immuno)therapy. Casein kinase 2 (CK2) is a serine/threonine protein kinase whose anti-apoptotic functions have been described in various hematological and solid tumors. Here we disclose an unanticipated role of CK2 in healthy human thymocytes that is selective to the γδ T-cell lineage. γδ thymocytes display higher (and T-cell receptor inducible) CK2 activity than their αβ counterparts, and are strikingly sensitive to death upon CK2 inhibition. Mechanistically, we show that CK2 regulates the pro-survival AKT signaling pathway in γδ thymocytes and, importantly, also in γδ T-cell acute lymphoblastic leukemia (T-ALL) cells. When compared with healthy thymocytes or leukemic αβ T cells, γδ T-ALL cells show upregulated CK2 activity, potentiated by CD27 costimulation, and enhanced apoptosis upon CK2 blockade using the chemical inhibitor CX-4945. Critically, this results in inhibition of tumor growth in a xenograft model of human γδ T-ALL. These data identify CK2 as a novel survival determinant of both healthy and leukemic γδ T cells, and may thus greatly impact their therapeutic manipulation.
PMCID: PMC5357576  PMID: 27899804
2.  Refractory coeliac sprue is a diffuse gastrointestinal disease 
Gut  2003;52(2):205-211.
Background: Refractory coeliac sprue (RCS) with an immunophenotypically aberrant clonal intraepithelial lymphocyte (IEL) population is considered a cryptic form of intestinal T cell lymphoma.
Aims: To investigate the distribution of the abnormal and monoclonal IEL population in the digestive tract of RCS patients.
Patients and methods: We compared the frequency of lymphocytic gastritis (LG) and lymphocytic colitis (LC), together with IEL phenotype and T cell clonality, in gastric and colonic samples from 15 adults with RCS (all with aberrant CD3 intracytoplasmic+ surface− CD8− clonal IELs on duodenojejunal biopsies), 18 patients with active coeliac disease (ACD), and 10 patients with coeliac disease (CD) on a gluten free diet (GFD-CD) by means of immunohistochemistry and multiplex polymerase chain reaction amplification of the T cell receptor γ gene (TCR-γ) rearrangement. Blood samples of nine RCS patients were also tested for clonality.
Results: LG was found in 9/14 (64%), 11/18 (61%), and 3/10 (30%) patients with RCS, ACD, and GFD-CD, respectively, while LC was found in 6/11 (55%), 3/4 (75%), and 2/3 (66%) patients. Contrary to CD, all samples from patients with LG and LC showed an aberrant IEL phenotype. Monoclonal TCR-γ rearrangements were detected in 8/13 (62%), 8/10 (80%), and 4/9 (44%) of gastric, colonic, and blood samples, respectively, from RCS patients, while in CD patients such rearrangements were only found in 2/25 (8%) gastric samples.
Conclusion: The immunophenotypically aberrant monoclonal IEL population present in the small intestine of patients with RCS frequently disseminates to the blood and the entire gastrointestinal epithelium, suggesting that this is a diffuse gastrointestinal disease.
PMCID: PMC1774980  PMID: 12524401
enteropathy-type intestinal T cell lymphoma; lymphocytic gastritis; lymphocytic colitis; coeliac disease; refractory sprue; T cell receptor gene rearrangement
3.  Molecular involvement of the pvt-1 locus in a gamma/delta T-cell leukemia bearing a variant t(8;14)(q24;q11) translocation. 
Molecular and Cellular Biology  1992;12(10):4751-4757.
A highly malignant human T-cell receptor (TCR) gamma/delta+ T-cell leukemia was shown to have a productive rearrangement of the TCR delta locus on one chromosome 14 and a novel t(8;14)(q24;q11) rearrangement involving the J delta 1 gene segment on the other chromosome 14. Chromosome walking coupled with pulsed-field gel electrophoretic (PFGE) analysis determined that the TCR J delta 1 gene fragment of the involved chromosome was relocated approximately 280 kb downstream of the c-myc proto-oncogene locus found on chromosome band 8q24. This rearrangement was reminiscent of the Burkitt's lymphoma variants that translocate to a region identified as the pvt-1 locus. Sequence comparison of the breakpoint junctions of interchromosomal rearrangements in T-cell leukemias involving the TCR delta-chain locus revealed novel signal-like sequence motifs, GCAGA(A/T)C and CCCA(C/G)GAC. These sequences were found on chromosome 8 at the 5' flanking site of the breakpoint junction of chromosome 8 in the TCR gamma/delta leukemic cells reported here and also on chromosome 1 in T-cell acute lymphocytic leukemia patients carrying the t(1;14)(p32;q11) rearrangement. These results suggest that (i) during early stages of gamma delta T-cell ontogeny, the region 280 kb 3' of the c-myc proto-oncogene on chromosome 8 is fragile and accessible to the lymphoid recombination machinery and (ii) rearrangements to both 8q24 and 1p32 may be governed by novel sequence motifs and be subject to common enzymatic mechanisms.
PMCID: PMC360402  PMID: 1406658
5.  Use of oligonucleotide probes directed against T cell antigen receptor gamma delta variable-(diversity)-joining junctional sequences as a general method for detecting minimal residual disease in acute lymphoblastic leukemias. 
Journal of Clinical Investigation  1990;86(6):2125-2135.
To provide a sensitive and generally applicable method to detect clonal cells in acute lymphoblastic leukemias (ALL), we have designed a new strategy based on the polymerase chain reaction (PCR) amplification of the T cell receptor gamma delta gene rearrangements found in most T and B lineage ALLs. PCR allows rapid sequencing of variable-(diversity)-joining (V-[D]-J) junctions from tumor DNA and construction of anti-junctional oligonucleotides (AJOs) used as probes to detect clonal cells in the same patient. We have defined oligonucleotides suitable for all T cell receptor (TCR) rearrangements involving functional V gamma segments. Oligonucleotides corresponding to preferential TCR delta rearrangements in T and B lineage ALLs were also used. By analysis of the nucleotide sequence of 52 V gamma-V gamma junctions from 30 cases of B and T ALLs, we demonstrate that V-J junctional sequences are clone specific in both lineages and at all stages of differentiation examined despite the frequent presence of the recently described P nucleotides. Experiments performed with TCR gamma delta AJOs on DNA from tumor cells and polyclonal T cells show that AJOs can be used to differentiate clonal cells from polyclonal T cells, distinguish between different T cell clones, and detect residual clonal populations at 10(-4)/10(-5) dilution. AJOs were also used to detect residual disease in samples from patients in clinical and morphological complete remission. Finally, rearrangement patterns were studied by classical Southern analysis in selected cases at both presentation and subsequent relapse showing absence of clonal evolution in most cases. V-(D)-J nucleotide sequences of rearrangements with an identical pattern of rearrangement at presentation and relapse were identical in all cases analyzed. We therefore describe a new, specific, and clinically useful strategy for the detection of minor clonal populations applicable in the majority of cases of ALL.
PMCID: PMC329853  PMID: 2174915
6.  Hypercalcaemia in chronic lymphatic leukaemia. 
Postgraduate Medical Journal  1986;62(727):393-394.
A 75 year old woman with a 13 year history of classical chronic lymphatic leukaemia (CLL) developed hypercalcaemia. Unlike previous reports, this was not associated with blastic transformation, hyperparathyroidism or features of multiple myeloma, but was due to classical CLL per se.
PMCID: PMC2418717  PMID: 3763549
7.  Incidence and clinical importance of bone marrow eosinophilia in Hodgkin's disease (BNLI Report No 29). British National Lymphoma Investigation. 
Journal of Clinical Pathology  1987;40(3):245-246.
A retrospective study of 136 bone marrow aspirates was undertaken before treatment to evaluate the importance of bone marrow eosinophilia in Hodgkin's disease. This occurred in 28 patients (21%) but did not correlate with age, sex, B symptoms, histopathological type or peripheral blood count. It also had no effect on survival. Bone marrow eosinophilia, therefore, seems to represent a common but non-specific reaction to Hodgkin's disease.
PMCID: PMC1140891  PMID: 3558856
8.  Selective peripheral blood eosinophilia associated with survival advantage in Hodgkin's disease (BNLI Report No 31). British National Lymphoma Investigation. 
Journal of Clinical Pathology  1987;40(3):247-250.
A peripheral blood eosinophilia was found at presentation in 193 of 1260 (15%) patients with Hodgkin's disease who had been entered into clinical studies by the British National Lymphoma Investigation (BNLI). Eosinophilia as a component of a general leucocytosis conferred no survival advantage. Eosinophilia without a general leucocytosis was present in 95 patients, and this selective eosinophilia was associated with a clear survival advantage. The association of selective eosinophilia and improved survival was limited to patients with mixed cellularity and grade I nodular sclerosis histology. Selective eosinophilia was found to be a good prognostic indicator both in local and generalised disease. Its survival advantage seemed to lie in the response to second line treatment following relapse.
PMCID: PMC1140892  PMID: 3558857
9.  Echovirus encephalitis and myositis in primary immunoglobulin deficiency. 
Two children are described with primary hypogammaglobulinaemia and encephalitis associated with echovirus infection. One also developed a condition resembling dermatomyositis which improved after he was given infusions of plasma containing antibody to the echovirus. Although both died of their encephalitis, the course of the brain disease in one of them may have been prolonged by treatment with specific antibody. These cases, together with another briefly mentioned case in an adult with congenital hypogammaglobulinaemia and echovirus infection, indicate that these patients are particularly susceptible to echoviruses.
PMCID: PMC1544838  PMID: 626516
10.  EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes 
Leukemia  2012;26(9):1908-1975.
Most consensus leukemia & lymphoma antibody panels consist of lists of markers based on expert opinions, but they have not been validated. Here we present the validated EuroFlow 8-color antibody panels for immunophenotyping of hematological malignancies. The single-tube screening panels and multi-tube classification panels fit into the EuroFlow diagnostic algorithm with entries defined by clinical and laboratory parameters. The panels were constructed in 2–7 sequential design–evaluation–redesign rounds, using novel Infinicyt software tools for multivariate data analysis. Two groups of markers are combined in each 8-color tube: (i) backbone markers to identify distinct cell populations in a sample, and (ii) markers for characterization of specific cell populations. In multi-tube panels, the backbone markers were optimally placed at the same fluorochrome position in every tube, to provide identical multidimensional localization of the target cell population(s). The characterization markers were positioned according to the diagnostic utility of the combined markers. Each proposed antibody combination was tested against reference databases of normal and malignant cells from healthy subjects and WHO-based disease entities, respectively. The EuroFlow studies resulted in validated and flexible 8-color antibody panels for multidimensional identification and characterization of normal and aberrant cells, optimally suited for immunophenotypic screening and classification of hematological malignancies.
PMCID: PMC3437410  PMID: 22552007
EuroFlow; antibody panel; lymphoma; flow cytometry; 8-color immunostaining; standardization; hematological malignancies
11.  EuroClonality/BIOMED-2 guidelines for interpretation and reporting of Ig/TCR clonality testing in suspected lymphoproliferations 
Leukemia  2012;26(10):2159-2171.
PCR-based immunoglobulin (Ig)/T-cell receptor (TCR) clonality testing in suspected lymphoproliferations has largely been standardized and has consequently become technically feasible in a routine diagnostic setting. Standardization of the pre-analytical and post-analytical phases is now essential to prevent misinterpretation and incorrect conclusions derived from clonality data. As clonality testing is not a quantitative assay, but rather concerns recognition of molecular patterns, guidelines for reliable interpretation and reporting are mandatory. Here, the EuroClonality (BIOMED-2) consortium summarizes important pre- and post-analytical aspects of clonality testing, provides guidelines for interpretation of clonality testing results, and presents a uniform way to report the results of the Ig/TCR assays. Starting from an immunobiological concept, two levels to report Ig/TCR profiles are discerned: the technical description of individual (multiplex) PCR reactions and the overall molecular conclusion for B and T cells. Collectively, the EuroClonality (BIOMED-2) guidelines and consensus reporting system should help to improve the general performance level of clonality assessment and interpretation, which will directly impact on routine clinical management (standardized best-practice) in patients with suspected lymphoproliferations.
PMCID: PMC3469789  PMID: 22918122
immunoglobulin; T-cell receptor; clonality; guideline; lymphoid malignancies
12.  The MLL recombinome of acute leukemias in 2013 
Leukemia  2013;27(11):2165-2176.
Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (∼90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.
PMCID: PMC3826032  PMID: 23628958
MLL; chromosomal translocations; translocation partner genes; acute leukemia; ALL; AML
13.  Effect of Avian Myeloblastosis Virus in the Japanese Quail 
Journal of Bacteriology  1966;92(4):1141-1149.
Moscovici, Carlo (University of Colorado Medical Center, Denver), and E. H. Macintyre. Effect of avian myeloblastosis virus in the Japanese quail. J. Bacteriol. 92:1141–1149. 1966.—Avian myeloblastosis virus (AMV) induced a spectrum of neoplasms in Japanese quail (Coturnix coturnix japonica) which was similar to that observed in the chicken, with one exception: the total absence of acute myeloblastic leukemia in quail. Studies in vivo as well as in vitro suggested that the cause for this difference may be ascribed to the heterogeneity of AMV and to the genetic makeup of the quail cell.
PMCID: PMC276389  PMID: 4288797

Results 1-13 (13)