Risk-adapted lymphoma treatment requires early and accurate assessment of prognosis. This investigation prospectively assessed the value of positron emission tomography with ...2-18Ffluoro-2-deoxy-D-glucose (FDG-PET) after two cycles of chemotherapy for prediction of progression-free survival (PFS) and overall survival (OS) in Hodgkin lymphoma (HL). Seventy-seven consecutive, newly diagnosed patients underwent FDG-PET at staging, after two and four cycles of chemotherapy, and after completion of chemotherapy. Median follow-up was 23 months. After two cycles of chemotherapy, 61 patients had negative FDG-PET scans and 16 patients had positive scans. Eleven of 16 FDG-PET–positive patients progressed and 2 died. Three of 61 FDG-PET–negative patients progressed; all were alive at latest follow-up. Survival analyses showed strong associations between early FDG-PET after two cycles and PFS (P < .001) and OS (P < .01). For prediction of PFS, interim FDG-PET was as accurate after two cycles as later during treatment and superior to computerized tomography (CT) at all times. In regression analyses, early interim FDG-PET was stronger than established prognostic factors. Other significant prognostic factors were stage and extranodal disease. Early interim FDG-PET is a strong and independent predictor of PFS in HL. A positive early interim FDG-PET is highly predictive of progression in patients with advanced-stage or extranodal disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
High-resolution genomic microarrays enable simultaneous detection of copy-number aberrations such as the known recurrent aberrations in chronic lymphocytic leukemia del(11q), del(13q), del(17p) and ...trisomy 12, and copy-number neutral loss of heterozygosity. Moreover, comparison of genomic profiles from sequential patients' samples allows detection of clonal evolution.
We screened samples from 369 patients with newly diagnosed chronic lymphocytic leukemia from a population-based cohort using 250K single nucleotide polymorphism-arrays. Clonal evolution was evaluated in 59 follow-up samples obtained after 5-9 years.
At diagnosis, copy-number aberrations were identified in 90% of patients; 70% carried known recurrent alterations, including del(13q) (55%), trisomy 12 (10.5%), del(11q) (10%), and del(17p) (4%). Additional recurrent aberrations were detected on chromosomes 2 (1.9%), 4 (1.4%), 8 (1.6%) and 14 (1.6%). Thirteen patients (3.5%) displayed recurrent copy-number neutral loss of heterozygosity on 13q, of whom 11 had concurrent homozygous del(13q). Genomic complexity and large 13q deletions correlated with inferior outcome, while the former was linked to poor-prognostic aberrations. In the follow-up study, clonal evolution developed in 8/24 (33%) patients with unmutated IGHV, and in 4/25 (16%) IGHV-mutated and treated patients. In contrast, untreated patients with mutated IGHV (n=10) did not acquire additional aberrations. The most common secondary event, del(13q), was detected in 6/12 (50%) of all patients with acquired alterations. Interestingly, aberrations on, for example, chromosome 6q, 8p, 9p and 10q developed exclusively in patients with unmutated IGHV.
Whole-genome screening revealed a high frequency of genomic aberrations in newly diagnosed chronic lymphocytic leukemia. Clonal evolution was associated with other markers of aggressive disease and commonly included the known recurrent aberrations.
In vivo distribution of myeloid transcription factors during granulopoiesis was investigated by Northern and Western blotting in 3 neutrophil precursor populations from human bone marrow: immature ...(myeloblasts MBs and promyelocytes PMs); intermediate mature (myelocytes MCs and metamyelocytes MMs); and mature neutrophil cells (band cells BCs and segmented neutrophil cells SCs). Nonneutrophil cells were removed with magnetic-bead–coupled antibodies against CD2, CD3, CD14, CD19, CD56, CD61, glycophorin-A, and CD49d (BCs/SCs) before RNA and protein extraction. Polymorphonuclear neutrophils (PMNs) from peripheral blood depleted with anti-CD49d antibodies were also included. Expression of acute myeloid leukemia 1b (AML-1b), c-myb, GATA-1, and CCAAT/enhancer binding protein γ (C/EBP-γ) was seen primarily in MBs/PMs, and little expression was found in more mature cells. The level of C/EBP-α was constant in the bone marrow–derived cells and decreased in PMNs. C/EBP-ϵ was found primarily in MCs/MMs and was almost absent in more mature cells. Expression of C/EBP-β, C/EBP-δ, and C/EBP-ζ was observed from the MC/MM stage onward, with peak levels in the most mature cells. The amount of PU.1 increased throughout maturation whereas the level of Elf-1 reached a nadir in MCs/MMs The PU.1 coactivator c-jun and c-jun’s dimerization partner c-fos were both detectable in MCs/MMs and increased in amount with maturity. CCAAT displacement protein (CDP) was found at comparable levels at all stages of differentiation. This demonstrates a highly individualized expression of the transcription factors, which can form the basis for the heterogeneous expression of granule proteins during granulopoiesis and cell cycle arrest in metamyelocytes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Antibodies against CD20 can activate complement and induce antibody-dependent cellular cytotoxicity (ADCC) in B lymphocytes. In B-cell lines, such antibodies also induce apoptosis. In this study, the ...expression and function of CD20 on B-cell chronic lymphocytic leukemia (B-CLL) cells were analyzed. Flow cytometric analysis demonstrated that B-CLL cells express CD20 with a fluorescence intensity that is significantly weaker than that of normal CD5+ and CD5− B cells and that of malignant CD5− low-grade non-Hodgkin lymphoma cells. A small population of cells from healthy donors that have an expression pattern of CD5 and CD20 identical to that of B-CLL cells were identified, and this population was confirmed to be of T lineage, not B lineage. Culture of freshly isolated B-CLL cells in the presence of the chimeric anti-CD20 antibody rituximab and a cross-linking F(ab)2 fragment, resulted in dose- and time-dependent induction of apoptosis. The induction of apoptosis occurred under conditions in which the influence of complement activation and ADCC was negligible. Cross-linking of rituximab induced strong and sustained phosphorylation of the 3 mitogen activated protein (MAP) kinases c-Jun NH2-terminal protein kinase, extracellular signal–regulated kinase, and p38. Introduction of the p38 inhibitor SB203580 into the system completely blocked signaling downstream of p38, as evidenced by the absence of MAPKAP K2 activity, and significantly reduced the degree of anti-CD20–induced apoptosis. These results demonstrate that cross-linking of rituximab bound to CD20 on freshly isolated B-CLL cells induces apoptosis through a signaling pathway that is dependent on p38 MAP-kinase activation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The expression levels of LPL, ZAP70, TCL1A, CLLU1 and MCL1 have recently been proposed as prognostic factors in chronic lymphocytic leukemia. However, few studies have systematically compared these ...different RNA-based markers.
Using real-time quantitative PCR, we measured the mRNA expression levels of these genes in unsorted samples from 252 newly diagnosed chronic lymphocytic leukemia patients and correlated our data with established prognostic markers (for example Binet stage, CD38, IGHV gene mutational status and genomic aberrations) and clinical outcome.
High expression levels of all RNA-based markers, except MCL1, predicted shorter overall survival and time to treatment, with LPL being the most significant. In multivariate analysis including the RNA-based markers, LPL expression was the only independent prognostic marker for overall survival and time to treatment. When studying LPL expression and the established markers, LPL expression retained its independent prognostic strength for overall survival. All of the RNA-based markers, albeit with varying ability, added prognostic information to established markers, with LPL expression giving the most significant results. Notably, high LPL expression predicted a worse outcome in good-prognosis subgroups, such as patients with mutated IGHV genes, Binet stage A, CD38 negativity or favorable cytogenetics. In particular, the combination of LPL expression and CD38 could further stratify Binet stage A patients.
LPL expression is the strongest RNA-based prognostic marker in chronic lymphocytic leukemia that could potentially be applied to predict outcome in the clinical setting, particularly in the large group of patients with favorable prognosis.
Numerous subsets of patients with chronic lymphocytic leukemia display similar immunoglobulin gene usage with almost identical complementarity determining region 3 sequences. Among IGHV4-34 cases, ...two such subsets with "stereotyped" B-cell receptors were recently identified, i.e. subset #4 (IGHV4-34/IGKV2-30) and subset #16 (IGHV4-34/IGKV3-20). Subset #4 patients appear to share biological and clinical features, e.g. young age at diagnosis and indolent disease, whereas little is known about subset #16 at a clinical level.
We investigated the global gene expression pattern in sorted chronic lymphocytic leukemia cells from 25 subset/non-subset IGHV4-34 patients using Affymetrix gene expression arrays.
Although generally few differences were found when comparing subset to non-subset 4/16 IGHV4-34 cases, distinct gene expression profiles were revealed for subset #4 versus subset #16. The differentially expressed genes, predominantly with lower expression in subset #4 patients, are involved in important cell regulatory pathways including cell-cycle control, proliferation and immune response, which may partly explain the low-proliferative disease observed in subset #4 patients.
Our novel data demonstrate distinct gene expression profiles among patients with stereotyped IGHV4-34 B-cell receptors, providing further evidence for biological differences in the pathogenesis of these subsets and underscoring the functional relevance of subset assignment based on B-cell receptor sequence features.
The existence of multiple subsets of chronic lymphocytic leukemia expressing 'stereotyped' B-cell receptors implies the involvement of antigen(s) in leukemogenesis. Studies also indicate that ...'stereotypy' may influence the clinical course of patients with chronic lymphocytic leukemia, for example, in subsets with stereotyped IGHV3-21 and IGHV4-34 B-cell receptors; however, little is known regarding the genomic profile of patients in these subsets.
We applied 250K single nucleotide polymorphism-arrays to study copy-number aberrations and copy-number neutral loss-of-heterozygosity in patients with stereotyped IGHV3-21 (subset #2, n=29), stereotyped IGHV4-34 (subset #4, n=17; subset #16, n=8) and non-subset #2 IGHV3-21 (n=13) and non-subset #4/16 IGHV4-34 (n=34) patients.
Over 90% of patients in subset #2 and non-subset #2 carried copy-number aberrations, whereas 75-76% of patients in subset #4 and subset #16 showed copy-number aberrations. Subset #2 and non-subset #2 patients also displayed a higher average number of aberrations compared to patients in subset #4. Deletion of 13q was the only known recurrent aberration detected in subset #4 (35%); this aberration was even more frequent in subset #2 (79%). del(11q) was more frequent in subset #2 and non-subset #2 (31% and 23%) patients than in subset #4 and non-subset #4/16 patients. Recurrent copy-number neutral loss-of-heterozygosity was mainly detected on chromosome 13q, independently of B-cell receptor stereotypy.
Genomic aberrations were more common in subset #2 and non-subset #2 than in subset #4. The particularly high frequency of del(11q) in subset #2 may be linked to the adverse outcome reported for patients in this subset. Conversely, the lower prevalence of copy-number aberrations and the absence of poor-prognostic aberrations in subset #4 may reflect an inherently low-proliferative disease, which would prevent accumulation of genomic alterations.
We analysed the regulation of G1-phase progression in relation to cytokine receptor signalling in HepG2 hepatoma cells, stably transduced with the IL-10 receptor after stimulation with Oncostatin M ...(OSM), IL-6, Leukaemia Inhibitory Factor (LIF) and IL-10. All cytokines induced STAT3 phosphorylation to approximately the same level, but only OSM, and to a lesser extent IL-6, induced STAT5 phosphorylation. The cytokines also stimulated phosphorylation of ERK in the order of decreasing effectiveness: OSM > IL-6 > LIF > IL-10. The same order of activity of the cytokines was observed on inhibition of DNA synthesis and accumulation of cells in the G1-phase of the cell cycle. These processes were accompanied by a decrease in cyclin A expression and CDK2 activity, and enhanced accumulation of p27kip1. The level of p27kip1 mRNA expression was unaffected by the cytokines, and maintenance of the elevated level of p27kip1 occurred independently of de novo protein synthesis. Furthermore, inhibition of proteasomal activity increased the level of p27kip1 in the unstimulated cells to the same level as in OSM-treated cells. Inhibition of MEK activation completely abrogated OSM and IL-6 induced p27kip1 accumulation, while expression of dominant negative STAT5 decreased the OSM and IL-6 mediated inhibition of DNA-synthesis and partially inhibited p27kip1 accumulation.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Large DNA viruses such as herpesvirus and poxvirus encode proteins that target and exploit the chemokine system of their host. These proteins have the potential to block or change the orchestrated ...recruitment of leukocytes to sites of viral infection. The genome of Kaposi sarcoma-associated herpes virus (KSHV) encodes three chemokine-like proteins named vCCL1, vCCL2, and vCCL3. In this study vCCL3 was probed in parallel with vCCL1 and vCCL2 against a panel of the 18 classified human chemokine receptors. In calcium mobilization assays vCCL1 acted as a selective CCR8 agonist, whereas vCCL2 was found to act as a broad spectrum chemokine antagonist of human chemokine receptors, including the lymphotactin receptor. In contrast vCCL3 was found to be a highly selective agonist for the human lymphotactin receptor XCR1. The potency of vCCL3 was found to be 10-fold higher than the endogenous human XCL1 chemokine in respect to phosphatidylinositol turnover and calcium mobilization as well as chemotaxis. High expression of XCR1 was found in placenta and neutrophils by real-time PCR. These data are consistent with reports of different expression profiles for vCCL2 and vCCL3 during the life cycle of KSHV, indicate a novel, sophisticated exploitation by the virus of specifically the lymphotactin receptor by both agonist and antagonist mechanisms, and suggest a unique physiological importance of this (somewhat overlooked) chemokine receptor.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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