Classification of primary cutaneous B-cell lymphomas: EORTC classification or REAL classification?
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Chromosome Aberrations↗
Biomedical subjects
R Willemze
Publications and source records attributed to R Willemze.
Secondary T-acute lymphoblastic leukaemia mimicking blast crisis in chronic myeloid leukaemia.
A 34-year-old man with chronic myeloid leukaemia (CML) firstly developed a lymphoid blast crisis of B-cell type. After a second chronic phase which lasted for > 4 years with maintenance chemotherapy of hydroxyurea, 6-mercaptopurine and methotrexate, he developed a T-cell acute lymphoblastic leukaemia of TcR-gammadelta+ type. Cytogenetic analysis revealed disappearance of the t(9;22) translocation and appearance of new abnormalities consistent with the diagnosis secondary acute leukaemia. To our knowledge, secondary leukaemia in CML has not previously been reported.
Adult↗
Human IP-9: A keratinocyte-derived high affinity CXC-chemokine ligand for the IP-10/Mig receptor (CXCR3).
Chemokines and their receptors play a crucial part in the recruitment of leukocytes into inflammatory sites. The CXC chemokines IP-10 and Mig are selective attractants for activated (memory) T cells, the predominant cell type in skin infiltrates in many inflammatory dermatoses. The selectivity for activated T cells can be explained by the fact that both chemokines exert their effects through a common receptor, CXCR3, which is nearly exclusively expressed on activated T cells. The aim of this study was to identify biologically active CXCR3 ligands produced by keratinocytes. To that end, Chinese hamster ovary cells expressing a cDNA encoding CXCR3 were challenged with proteins obtained from interferon-gamma stimulated keratinocytes and subsequently monitored for effects on second messenger systems. By this approach we were able to isolate IP-10 and Mig, and in addition identified a novel highly potent ligand for the CXCR3 receptor, designated interferon-gamma-inducible protein-9, which proved to be chemotactic for activated T cells expressing CXCR3. Protein sequence and mass spectrometric analysis followed by molecular cloning of the cDNA encoding interferon-gamma-inducible protein-9, revealed that interferon-gamma-inducible protein-9 is a CXC chemokine with a molecular mass of 8303 Da. From a GenBank database query it became clear that interferon-gamma-inducible protein-9 is in fact the protein encoded by the cDNA sequence also known as beta-R1, H174 or I-TAC. In situ hybridization experiments showed that interferon-gamma-inducible protein-9 mRNA is expressed by basal layer keratinocytes in a variety of skin disorders, including allergic contact dermatitis, lichen planus, and mycosis fungoides suggesting a functional role for this chemokine in skin immune responses.
Amino Acid Sequence↗
The CXCR3 activating chemokines IP-10, Mig, and IP-9 are expressed in allergic but not in irritant patch test reactions.
Differentiation between allergic and irritant contact dermatitis reactions is difficult, as both inflammatory diseases are clinically, histologically, and immunohistologically very similar. Previous studies in mice revealed that the chemokine IP-10 is exclusively expressed in allergic contact dermatitis reactions. In the present study, we investigated whether the mRNA expression of IP-10 and the related CXCR3 activating chemokines, Mig and IP-9 are also differentially expressed in human allergic contact dermatitis and irritant contact dermatitis reactions. Skin biopsies from allergic (13 cases) and sodium lauryl sulfate-induced irritant patch test reactions (13 cases), obtained 1-72 h after patch testing, were studied by means of an in situ hybridization technique. Results of chemokine mRNA expression were correlated with clinical scoring, histology, and immunohistochemical data including the proportion of inflammatory cells expressing CXCR3, the receptor for IP-10, Mig, and IP-9, and ICAM-1 and HLA-DR expression on keratinocytes. IP-10, Mig, and IP-9 mRNA were detected in seven of nine allergic contact dermatitis reactions after 24-72 h, but not in sodium lauryl sulfate-induced irritant contact dermatitis reactions. ICAM-1 expression by keratinocytes was only found in allergic contact dermatitis reactions and correlated with chemokine expression. Moreover, up to 50% of the infiltrating cells in allergic contact dermatitis expressed CXCR3, in contrast to only 20% in irritant contact dermatitis reactions. In conclusion, we have demonstrated differences in chemokine expression between allergic contact dermatitis and irritant contact dermatitis reactions, which might reflect different regulatory mechanisms operating in these diseases and may be an important clue for differentiation between allergic contact dermatitis and irritant contact dermatitis reactions.
Chemokine CXCL10↗
EORTC classification for primary cutaneous lymphomas: the best guide to good clinical management. European Organization for Research and Treatment of Cancer.
In 1997 the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer (EORTC) published a proposal for a classification for the group of primary cutaneous lymphomas (1). The EORTC classification is the first and only classification that is designed exclusively for the group of primary cutaneous lymphomas. It is also the only classification that has been clinically validated for this group of diseases. As illustrated by this special issue, this classification has resulted not only in the discussion of the definition and terminology of some types of cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma (CBCL), but also in a discussion of whether organ-based classification schemes (separate from existing hematopathologic classification schemes for non-Hodgkin lymphomas) should be used. This article explains why it was necessary to create a separate classification for the group of primary cutaneous lymphomas. A short introduction on the history of the classification of cutaneous lymphomas is provided. Next, the basic principles of the EORTC classification are presented. Finally, controversies between the EORTC classification versus the REAL classification (2) and the proposed WHO classification (3), which still impede the usage of one common classification system, are discussed.
Humans↗
Mechanisms underlying hematopoietic stem cell mobilization induced by the CXC chemokine interleukin-8.
The CXC chemokine interleukin-8 induces rapid mobilization of hematopoietic progenitor cells in mice and monkeys. Antibodies against the beta 2-integrin leukocyte function-associated antigen-1 completely blocked interleukin-8-induced mobilization. This was not due to a direct effect on the hematopoietic progenitor cells, as leukocyte function-associated antigen-1 was found not to be expressed on hematopoietic progenitor cells. Additional experiments showed that interleukin-8 induces the rapid release of the metalloproteinase gelatinase B, concurrent with the mobilization of hematopoietic progenitor cells. Mobilization could be completely prevented by anti-gelatinase B antibodies. Because neutrophils express leukocyte function-associated antigen-1 and high affinity interleukin-8 receptors, and release gelatinase B upon stimulation with interleukin-8, we hypothesized that neutrophils are key mediators in interleukin-8-induced stem cell mobilization. Further studies showed that mobilization by interleukin-8 was completely absent in mice rendered neutropenic with anti-granulocytic antibodies. Taken together, these data are consistent with an essential role for neutrophils in interleukin-8-induced stem cell mobilization.
Animals↗
A cytotoxic phenotype does not predict clinical outcome in anaplastic large cell lymphomas.
AIM: To investigate whether anaplastic large cell lymphomas (ALCL) expressing cytotoxic proteins have a relatively worse clinical outcome compared with ALCL lacking a cytotoxic phenotype. METHODS: 59 primary cases of ALCL originating from different sites were investigated by immunohistochemistry for the presence of the cytotoxic proteins T cell intracytoplasmic antigen (TIA-1) and granzyme B in the neoplastic cells. Since site of origin and expression of anaplastic lymphoma kinase (ALK) strongly influence prognosis, the presence of a cytotoxic phenotype was also investigated in relation to the primary site of origin (lymph node, gut, or skin) and ALK expression. The prognostic value was investigated by analysis of overall and relapse-free survival time, including Cox regression analysis. RESULTS: 39 of 59 ALCL (66%) appeared to have a cytotoxic phenotype as shown by expression of TIA-1 or granzyme B or both in the neoplastic cells. The presence of a cytotoxic phenotype did not have any influence on prognosis. Even when the survival data were corrected for site of origin and stage at presentation or were analysed separately for ALK positive and negative cases, no prognostic influence of a cytotoxic phenotype was observed. CONCLUSIONS: In primary biopsies of patients with ALCL, the presence of a cytotoxic phenotype is not related to clinical outcome of the disease.
Adult↗
Treatment of multifocal primary cutaneous B-cell lymphoma: a clinical follow-up study of 29 patients.
PURPOSE: Although patients with primary cutaneous B-cell lymphoma (CBCL) and localized skin lesions are generally treated with radiotherapy and have an excellent prognosis, the clinical behavior and optimal treatment of CBCL presenting with multifocal skin lesions are less well defined. In this study, we evaluated the clinical behavior of and results of treatment for multifocal CBCL in 29 patients, and we formulated therapeutic guidelines. PATIENTS AND METHODS: The study group included 16 patients with primary cutaneous follicular center-cell lymphoma (PCFCCL), eight with primary cutaneous immunocytoma (PCI), and five with primary cutaneous large B-cell lymphoma presenting on the legs (PCLBCL of the leg). RESULTS: Only one of the 24 patients with multifocal PCFCCL or PCI developed extracutaneous disease, and no patient died from lymphoma (median follow-up, 54 months). In patients with PCFCCL, treatment with either multiagent chemotherapy (nine patients) or radiotherapy directed toward all skin lesions (five patients) proved equally effective in terms of complete remission, relapse, and survival. In contrast, all five patients with PCLBCL of the leg developed extracutaneous disease, and four of the five died from systemic lymphoma, 8 to 36 months (median, 21 months) after diagnosis. CONCLUSION: The results of these preliminary studies suggest that patients with PCFCCL or PCI presenting with multifocal skin lesions have the same excellent prognosis that patients with localized PCFCCL or PCI have and that radiotherapy directed toward all skin lesions is as effective as multiagent chemotherapy. Patients with PCLBCL of the leg have a more unfavorable prognosis, particularly patients presenting with multifocal skin lesions. This last group should always be treated with multiagent chemotherapy.
Adult↗
VH gene analysis of primary cutaneous B-cell lymphomas: evidence for ongoing somatic hypermutation and isotype switching.
Primary cutaneous B-cell lymphomas are B-cell non-Hodgkin's lymphomas that arise in the skin. The major subtypes discerned are follicle center cell lymphomas, immunocytomas (marginal zone B-cell lymphomas), and large B-cell lymphomas of the leg. In this study, we analyzed the variable heavy chain (VH) genes of 7 of these lymphomas, ie, 4 follicle center cell lymphomas (diffuse large-cell lymphomas) and 3 immunocytomas. We show that all these lymphomas carry heavily mutated VH genes, with no obvious bias in VH gene usage. The low ratios of replacement versus silent mutations observed in the framework regions of 5 of the 7 lymphomas suggest that the structure of the B-cell antigen receptor was preserved, as in normal B cells that are selected for antibody expression. Moreover, evidence for ongoing mutation was obtained in 3 immunocytomas and in one lymphoma of large-cell type. In addition, in 1 immunocytoma, both IgG- and IgA-expressing clones were found, indicative of isotype switching. Our data provide insight into the biology of primary cutaneous B-cell lymphomas and may be of significance for their classification.
Codon↗
T cells recognizing leukemic CD34(+) progenitor cells mediate the antileukemic effect of donor lymphocyte infusions for relapsed chronic myeloid leukemia after allogeneic stem cell transplantation.
Adoptive immunotherapy with donor lymphocyte infusions (DLI) is an effective treatment for relapsed chronic myeloid leukemia (CML) after allogeneic stem cell transplantation. To identify the effector and target cell populations responsible for the elimination of the leukemic cells in vivo we developed an assay to measure the frequency of T lymphocyte precursor cells capable of suppressing leukemic progenitor cells. Target cells in this assay were CML cells that were cultured in the presence of stem cell factor, interleukin 3, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and erythropoietin. [3H]thymidine incorporation at day 7 represented the proliferation of the progeny of the CD34(+) CML progenitor cells, and not of the more mature CD34(-) CML cells. Effector cells were mononuclear cells, which were used in a limiting dilution analysis to measure the frequencies of CML progenitor cell-inhibitory lymphocyte precursors (PCILp) in peripheral blood of seven patients before and after DLI for relapsed CML. In the six patients who entered complete remission, a 5- to 100-fold increase of PCILp was found during the clinical response. In the patient with resistant relapse the frequency of PCILp was <10 per ml before and after DLI. Leukemia-reactive helper T lymphocyte precursor frequencies remained unchanged after DLI. A significant increase in cytotoxic T lymphocyte precursor frequency against more mature leukemic cells was found in only two responding patients. These results indicate that T cells specifically directed against CD34(+) CML progenitor cells mediate the antileukemic effect of DLI.
Antigens, CD34↗
Assessment of telomere length in hematopoietic interphase cells using in situ hybridization and digital fluorescence microscopy.
Telomeres are G/C-rich repetitive DNA sequences at the end of all eukaryotic chromosomes. The loss of telomeric repeat sequences during cell divisions has been proposed as a possible mechanism for cell senescence. The standard procedure for measurement of telomere length is Southern blot (SB) hybridization with a telomere-specific probe. However, in using this technique no information can be obtained on variation in telomeric fragments due to interchromosomal, intrachromosomal, and intercellular differences. Lansdorp et al. (Hum Mol Genet 5:685-691, 1996) developed a method to measure individual telomeres, using in situ hybridization on metaphase chromosomes, employing peptide nucleic acid (PNA) probes and digital fluorescence microscopy. In this paper we describe a method that can be used to assess telomeric length in interphase cells. An algorithm was developed to measure the total intranuclear fluorescence in situ hybridization (FISH) signal, which features accurate correction for the local autofluorescence. Application of this methodology to samples of fetal liver, umbilical cord blood, and adult bone marrow cells showed a gradual decrease of average telomeric length. Southern blot analysis and PNA FISH measurements on chromosomes in the same samples showed similar results. Advantages of interphase measurements include the possibility of studying nonproliferating cells, thus avoiding selection and cell culturing.
Adult↗
Anti-LFA-1 blocking antibodies prevent mobilization of hematopoietic progenitor cells induced by interleukin-8.
Previously, we have shown that interleukin (IL)-8 induces the rapid (15 to 30 minutes) mobilization of hematopoietic progenitor cells (HPC) in mice. Because integrins are essential for adhesion and transendothelial migration of HPC, we studied the involvement of the beta2-integrin leukocyte function-associated antigen-1 (LFA-1) in IL-8-induced mobilization. After a single injection of blocking anti-LFA-1 antibodies, no mobilization of colony-forming cells was observed. In addition, when mice were pretreated with anti-LFA-1 or saline and subsequently injected with 30 microg of IL-8, mobilization of HPC was completely blocked. We showed that this was not due to anti-LFA-1 antibodies affecting colony formation, as addition of anti-LFA-1 antibodies to colony cultures in semisolid medium had no inhibitory activity. Also, anti-intercellular adhesion molecule (ICAM)-1 antibodies, directed to the main ligand of LFA-1 significantly inhibited the IL-8-induced mobilization. Furthermore, IL-1-induced mobilization was significantly inhibited by anti-LFA-1 antibodies. Because LFA-1 is reported to be expressed on more differentiated HPC, it was considered that the IL-8-induced mobilization of more primitive HPC would not be blocked by anti-LFA-1 antibodies. Transplantation of blood-derived mononuclear cells (MNC) from IL-8-mobilized animals pretreated with anti-LFA-1 antibodies protected only 25% of lethally irradiated recipient mice, whereas the radioprotection rate of control mice transplanted with MNC derived from IL-8-mobilized animals was 86% (P < .01). Anti-LFA-1 antibodies did not interfere with stem cell homing, as transplantation of IL-8-mobilized blood MNC, incubated in vitro with these antibodies resulted in 100% radioprotection. We conclude that anti-LFA-1 antibodies completely prevent the rapid mobilization of colony-forming cells and of cells with radioprotective capacity induced by IL-8. These results indicate a major role for the beta2-integrin LFA-1 in the IL-8-induced mobilization of hematopoietic stem cells.
Animals↗
Correction of abnormal T-cell receptor repertoire during interferon-alpha therapy in patients with hairy cell leukemia.
Patients with the B-cell malignancy hairy cell leukemia (HCL) exhibit a skewed T-cell repertoire with oligoclonal expression or absence of many members of the T-cell receptor (TCR) BV gene families. To evaluate whether interferon-alpha (IFN-alpha) therapy would not only restore normal hematopoiesis, but also the abnormal T-cell repertoire, we studied T lymphocytes from a cohort of HCL patients treated by IFN-alpha in the past, at initiation, and at several intervals up to 6 years of IFN-alpha treatment. The junctional regions from 22 TCRBV gene families were analyzed after polymerase chain reaction amplification of cDNA (RT-PCR) using family specific primers. In all seven patients improvement of the skewed T-cell repertoire was not seen until 2 years of treatment. It consisted of disappearance of oligoclonal subpopulations and (polyclonal) reappearance of absent TCRBV gene families. The RT-PCR results were correlated with the TCRBV protein expression using TCRBV-specific monoclonal antibodies. T lymphocytes from four patients with active HCL contained large expansions of particular TCRBV-expressing cells (up to 25% of the CD3+ cells; 600 to 700/microL whole blood), which decreased during IFN-alpha therapy in both patients tested. Finally, restoration of the TCR repertoire matched normalization of the functional immune repertoire as measured by proliferative, helper, and cytotoxic T-lymphocyte precursor frequencies against major histocompatibility complex-unrelated individuals. In conclusion, oligoclonal bands of TCRBV gene families found by RT-PCR correspond with a dramatic increase in circulating T lymphocytes expressing the same TCRBV family. Moreover, IFN-alpha can restore the skewed T-cell repertoire and suppress persistent T-cell clones upon treatment of the accompanying malignancy.
Adult↗
The early phase of engraftment after murine blood cell transplantation is mediated by hematopoietic stem cells.
Blood cells transplantation is largely replacing bone marrow transplantation because engraftment is more rapid. This accelerated engraftment is thought to be mediated by relatively mature committed hematopoietic progenitor cells. Herein, we have used a modified rhodamine (Rho) staining procedure to identify and purify Rho+/++ (dull/bright) and Rho- (negative) subpopulations of hematopoietic progenitor cells in murine cytokine-mobilized blood. The Rho+/++ cell population contained > 99% of committed progenitor cells with in vitro colony-forming ability. The Rho- cell population contained the majority of hematopoietic stem cells with in vivo marrow repopulating ability. The rate of hematopoietic reconstitution was identical in recipients of grafts containing only purified Rho- stem cells or purified Rho- stem cells in combination with large numbers of Rho+/++ committed progenitor cells. In contrast, transplantation of 3-fold more hematopoietic stem cells resulted in accelerated reconstitution, indicating that the reconstitution rate was determined by the absolute numbers of Rho- stem cells in the graft. In addition, we observed a 5- to 8-fold reduced frequency of the subset of hematopoietic stem cells with long-term repopulating ability in cytokine-mobilized blood in comparison to steady-state bone marrow. Our results indicate that hematopoietic stem cells and not committed progenitor cells mediate early hematopoietic reconstitution after blood cell transplantation and that relative to bone marrow, the frequency of stem cells with long-term repopulating ability is reduced in mobilized blood.
Animals↗
Sublocalization of the breakpoints of a t(5;16) in myelodysplasia.
As a first step in characterizing a t(5;16)(q31;p11.2) in a patient with the diagnosis refractory anemia with ring sideroblasts, a cell fusion was carried out between bone marrow cells from the patient and the Chinese hamster cell line A3. Using PCR and FISH analysis on hybrid lines containing the human derivative 16 chromosome, the breakpoints could be mapped between the markers TCF-7 and IL-9 on chromosome 5 and OL-7 and s30A4 on chromosome 16, both regions spanning approximately 1 Mb. Since the breakpoint on 5q has occurred in a region that is frequently deleted in myeloid malignancies, the gene disrupted by this translocation could also be implicated in this aberration.
Animals↗
Differences in Epstein-Barr virus expression between primary and secondary cutaneous angiocentric lymphomas. French Study Group of Cutaneous Lymphomas.
BACKGROUND: Epstein-Barr virus (EBV) has been demonstrated in angiocentric immunoproliferative lesions, suggesting that it could be a causative factor. We investigated for the presence of EBV in 12 primary and 2 secondary cutaneous angiocentric lymphomas (CALs). OBSERVATIONS: In the 2 secondary CALs, strong reactivity for EBV RNAs and latent membrane protein 1 were detected on paraffin-embedded sections. In contrast, 10 of 12 primary CALs were completely negative for EBV RNAs and latent membrane protein 1. In 2 primary CALs, EBV RNAs and latent membrane protein 1 were detected in few tumor cells. In the group of primary CALs, 8 of 12 were still alive at last follow-up, 3 died of systemic lymphoma, and 1 died of another cause, whereas both patients with secondary CALs died of disease within 1 year. CONCLUSION: Differences in the presence of EBV and clinical behavior between primary and secondary CALs suggest that different mechanisms are operative in the pathogenesis of these conditions, and indicate that the 2 groups should be considered separately.
Adult↗
Selective response of CD5+ B cell malignancies to activation of the CD72 antigen.
The function of the simultaneous expression of CD5 and its ligand CD72 on B cell malignancies like chronic lymphocytic leukemia and mantle cell lymphoma was assessed. It is unknown if reciprocal interactions between CD72 and CD5 exert an autocrine growth-promoting or -inhibiting effect. CD5+ (n = 13) and CD5- (n = 9) B cell malignancies were cultured with the anti-CD72 mAb WL225. For comparison, five other anti-CD72 mAbs were tested. Only CD5+ B cell malignancies proliferated upon CD72 activation (9 out of 13 cases). A strong suppressive effect of IL-4 on the anti-CD72-induced [3H]thymidine incorporation, partially caused by downmodulation of the CD72 expression, was seen. Stimulation of the CD5 antigen by L cells transfected with human CD72 (LhCD72) and the anti-CD5 mAb 1C12 exerted no (n = 9) or a minor effect (2 out of 8 cases), respectively. Finally, the results of CD72 stimulation were compared with CD40 stimulation, as this "CD40 system" is an effective method for stimulating B cell malignancies. In 4 of the 7 anti-CD72 responsive cases a costimulatory effect was seen.
Antigens, CD↗
Chemokine IP-10 expression in cultured human keratinocytes.
IP-10, a member of the CXC family of chemokines, is considered to play an important role in inflammation via its T-cell chemotactic and adhesion-promoting properties. Elevated IP-10 levels in the epidermis of psoriasis, delayed-type hypersensitivity reactions, cutaneous T-cell lymphoma and fixed drug eruptions prompted us to study its expression in keratinocytes. IP-10 mRNA could be detected using the sensitive RT-PCR method, but not by Northern blotting in RNA preparations from unstimulated normal cultured keratinocytes, indicating a low steady-state level of IP-10 mRNA. Upon stimulation with IFN-gamma, IP-10 mRNA was found to accumulate in high amounts in a time- and dose-dependent manner. Superexpression was found with the combination of IFN-gamma and TNF-alpha or IL-1, although these latter cytokines by themselves did not induce accumulation of IP-10 mRNA. Nuclear run-on experiments performed to investigate the regulation of IP-10 mRNA expression, showed a very high constitutive transcriptional activity of the IP-10 gene in unstimulated keratinocytes, which was not affected by stimulation with IFN-gamma, TNF-alpha, or a combination of IFN-gamma and TNF-alpha. Protein kinase C (PKC) was shown to be involved in IP-10 mRNA expression since the PKC inhibitor H7 decreased IP-10 mRNA accumulation. A protein was isolated from culture supernatants of stimulated keratinocytes using HPLC techniques and, by sequence analysis, was found to be identical to IP-10. The dynamics of secretion of IP-10 protein as monitored by ELISA was shown to parallel the mRNA expression.
Antineoplastic Agents↗