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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We here present an extremely rare case of granular lymphocytic leukemia derived from gamma delta T-cell (gamma delta T-GLL). The blood picture at diagnosis was as follows; white cell count 25.7 x 10(9)/l containing 94% atypical lymphocytes with cytoplasmic granules, hemoglobin 11.8 g/dl and platelet count 124 x 10(9)/l. The atypical lymphocytes were positive for CD2, CD3, CD5, CD7, CD56 and TCR gamma delta, but negative for CD4, CD8, CD57, TCR alpha beta and B-cell antigens. The cytotoxic molecules, T-cell intracellular antigen-1 (TIA-1) and granzyme B, were positive by immunocytochemical analysis. Southern blot analysis showed rearrangement of T-cell receptor J gamma and C beta genes but germline configuration of the JH gene. Neither serum antibody against human T-cell leukemia virus type-I (HTLV-I) nor the integration of HTLV-I proviral DNA was detected. CT scan showed splenomegaly but no lymph node enlargement. A diagnosis of gamma delta T-GLL was made, and she has been followed up without any therapies for more than 4 years.
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PMID:Granular lymphocytic leukemia derived from gamma delta T-cell expressing cytotoxic molecules. 1122 23

Recently, we demonstrated that the presence of high percentages of activated cytotoxic T-lymphocytes (CTLs) in biopsy specimens of both Hodgkin's disease (HD) and ALK negative anaplastic large cell lymphoma (ALCL) is associated with a poor prognosis. To test whether this biological prognostic factor is more important in predicting clinical outcome than histological diagnosis or clinical factors, we compared the prognostic value of these parameters in an expanded group of classical HD and ALK negative ALCL. Tumor biopsies of classical HD (n = 83) and ALK negative systemic nodal ALCL (n = 43) were investigated for the presence of activated CTLs by immunohistochemistry, using a monoclonal antibody directed against granzyme B. Percentages of activated CTLs were quantified using Q-PRODIT, and their prognostic value was compared to that of histological diagnosis and clinical parameters, including age and stage. Both in classical HD and ALK negative ALCL, a high percentage of activated CTLs (ie > or = 15%) identified a group of patients with poor overall and progression-free survival time, even when adjusted for stage. In multivariate analysis, percentage of activated CTLs remained a strong independent prognostic marker, and was more sensitive than histological diagnosis or clinical factors in predicting overall survival time. We conclude that a high percentage of activated CTLs in the reactive infiltrate of ALK negative ALCL and classical HD is a strong indicator for an unfavorable clinical outcome, regardless of histological diagnosis or clinical parameters. As such, this biological parameter may be an especially helpful tool to determine therapeutic strategies in cases in which the differentiation between ALK negative ALCL and HD remains difficult.
Leukemia 2001 Mar
PMID:Percentage of activated cytotoxic T-lymphocytes in anaplastic large cell lymphoma and Hodgkin's disease: an independent biological prognostic marker. 1123 71

This report describes an unusual extramedullary hematologic malignancy in an 18-month-old child who presented with a capillary leak syndrome that evolved into hyperleukocytosis with malignant cells. The circulating tumor cells did not express an antigen profile typical of any subtype of leukemia commonly observed in children. Tumor cells were CD3(-)/CD56(+); had germline TCR genes; and strongly expressed CD30, epithelial membrane antigen, and anaplastic lymphoma kinase (ALK) consistent with a null cell anaplastic large cell lymphoma (ALCL). The malignant cells contained a t(2;19)(p23;p13.1) that interrupted ALK and translocated it to the der(19). Reverse transcriptase-polymerase chain reaction and nucleotide sequence analysis revealed fusion of ALK to tropomyosin 4, an ALK fusion partner not described previously in hematologic malignancies. The clinical presentation and phenotypic features of this malignancy were not typical for ALCL because tumor cells expressed both myeloid (CD13, CD33, HLA-DR) and natural killer (NK) cell antigens. The neoplastic cells most resembled NK cells because in addition to being CD3(-)/CD56(+) with germline TCR genes, these cells were CD25(+)/CD122(+)/granzyme B(+) and possessed the functional properties of immature NK cells. The unusual clinical presentation, immunophenotype, and functional properties of these neoplastic cells suggest that this malignancy may be derived from the putative myeloid-NK precursor cell. Furthermore co-expression of NK and ALCL features supports the concept that a minority of null-ALCL may be derived from NK cells and expands the spectrum of phenotypes that can be seen in tumors produced by ALK fusion proteins. (Blood. 2001;98:1209-1216)
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PMID:Unusual childhood extramedullary hematologic malignancy with natural killer cell properties that contains tropomyosin 4--anaplastic lymphoma kinase gene fusion. 1149 72

A 67-year-old man was admitted with erythematous skin papules, lymphadenopathy and liver dysfunction. The bone marrow was filled with atypical lymphoid cells, and a skin biopsy showed diffuse dermal infiltration of neoplastic cells, which were positive for CD2, CD8, CD56, TIA-1, Granzyme B and EBER (ISH), but negative for CD3, CD4, CD16 and CD57. Molecular analysis showed a germline configuration for T-cell receptor beta, gamma chain genes, and monoclonal integration of Epstein-Barr virus. The THP-COP regimen was not effective and the patient died of severe metabolic acidosis 2 months later. Autopsy revealed diffuse infiltration of neoplastic cells in almost all organs. Apoptosis of tumor cells and proliferation of hemophagocytic macrophages were remarkable. Neither angiocentricity nor necrosis was observed. The findings in this patient were indistinguishable from advanced-stage nasal-type NK cell lymphoma. However, the diagnosis of aggressive NK cell leukemia/lymphoma may be justified because of the marked involvement of the marrow at onset, fulminant clinical course and diffuse infiltration of tumor cells evident at autopsy.
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PMID:[Aggressive NK cell leukemia/lymphoma: an autopsy case]. 1157 1

Unlike other leukemia types in which the bone marrow findings are diagnostic, the bone marrow pathology of T-cell granular lymphocytic leukemia (GLL) is subtle and ill-defined. In this study, bone marrow biopsy specimens from 36 patients with T-cell GLL and from 25 control patients with cytopenias and relative or absolute increases in blood large granular lymphocytes were studied by immunohistochemistry using antibodies to the cytolytic lymphocyte antigens CD8, CD56, CD57, TIA-1, and granzyme B. The goals were to clarify the bone marrow pathology of T-cell GLL and to refine the diagnostic criteria for T-cell GLL. Most bone marrow specimens from the T-cell GLL patients contained interstitially distributed clusters of at least 8 CD8(+) (83%) or TIA-1(+) (75%) lymphocytes or clusters of at least 6 granzyme B(+) (50%) lymphocytes. Interstitial clusters of CD8(+), TIA-1(+), or granzyme B(+) cells were present in 36%, 12%, and 0%, respectively, of the control bone marrows (all values significantly different, P <.001). An additional T-cell GLL disease-specific finding was the presence of linear arrays of intravascular CD8(+), TIA-1(+), or granzyme B(+) lymphocytes, found in 67% of cases of T-cell GLL and in none of the 25 control samples (P <.001). Staining for CD56 and CD57 was noncontributory. These findings clarify the bone marrow histopathology of T-cell GLL and provide an additional tool by which the discrete, abnormal lymphocyte population required for a diagnosis of T-cell GLL can be identified.
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PMID:Distinct bone marrow findings in T-cell granular lymphocytic leukemia revealed by paraffin section immunoperoxidase stains for CD8, TIA-1, and granzyme B. 1175 81

The endogenous viral superantigen 7 in DBA/2 mice serves as a target antigen on syngeneic ESb-MP lymphoma cells for allogeneic graft-vs-leukaemia reactive cells. Allogeneic viral superantigen 7 reactive Vbeta6+ T cells are able to transfer graft-vs-leukaemia reactivity and to kill specifically viral superantigen 7+ ESb-MP tumour cells in vitro. Here we elucidate the mechanism of this superantigen specific cell lysis. Already 10 min after co-incubation with in vitro stimulated Vbeta6+ T cells, viral superantigen 7+ ESb-MP tumour cells show an apoptotic phenotype (Annexin V-positivity, DNA-fragmentation). This extremely rapid type of cell death is not mediated by the death inducing ligands CD95L, TRAIL and TNF but by perforin and granzyme B. Surprisingly, neither mitochondria nor any of the known caspases appear to be involved in this type of tumour cell killing. In contrast, nitric oxide, released by activated macrophages and endothelial cells, induces in the same tumour cells another type of apoptosis which is much slower and involves mitochondria and caspase activation. A synergistic effect between the two different effector mechanisms of superantigen reactive donor cytotoxic T lymphocytes and nitric oxide releasing host macrophages and endothelial cells might explain the effective immune rejection of even advanced metastasised cancer in this graft-vs-leukaemia animal model.
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PMID:Superantigen reactive Vbeta6+ T cells induce perforin/granzyme B mediated caspase-independent apoptosis in tumour cells. 1187 49

Wilms tumor gene product WT1 and proteinase 3 are overexpressed antigens in acute myeloid leukemia (AML), against which cytotoxic T lymphocytes can be elicited in vitro and in murine models. We performed this study to investigate whether WT1- and proteinase 3-specific CD8 T cells spontaneously occur in AML patients. T cells recognizing HLA-A2.1-binding epitopes from WT1 or proteinase 3 could be detected ex vivo in 5 of 15 HLA-A2-positive AML patients by interferon-gamma (IFN-gamma) ELISPOT assay and flow cytometry for intracellular IFN-gamma and in 3 additional patients by flow cytometry only. T cells producing IFN-gamma in response to proteinase 3 were further characterized in one patient by 4-color flow cytometry, identifying them as CD3(+)CD8(+)CD45RA(+) CCR7(-) T cells, resembling cytotoxic effector T cells. In line with this phenotype, most of the WT1- and proteinase-reactive T cells were granzyme B(+). These results provide for the first time evidence for spontaneous T-cell reactivity against defined antigens in AML patients. These data therefore support the immunogenicity of WT1 and proteinase 3 in acute leukemia patients and the potential usefulness of these antigens for leukemia vaccines.
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PMID:CD8 T-cell responses to Wilms tumor gene product WT1 and proteinase 3 in patients with acute myeloid leukemia. 1220 Mar 77

The diagnosis of granular lymphocytic leukaemia (GLL) requires the presence of an immunophenotypically distinct T-cell (T-GLL) or natural killer-cell (NK-GLL) population. Flow cytometric immunophenotyping was performed on 21 T-GLL patients, 11 NK-GLL patients and 20 normal control subjects using antibodies to T and NK cell-associated antigens in order to accurately identify the distinguishing features of T-GLL and NK-GLL. The NK antigens evaluated included: CD16, CD57, CD94, CD161, and the killing inhibitory receptors (KIRs) CD158a, CD158b and CD158e (p70). Abnormal T-antigen expression was present in all T-GLL patients. CD57 was frequently expressed in T-GLL, however, one-third of patients showed partial CD57 expression similar to that seen in T cells from normal control subjects. Ten T-GLL were KIR positive; all expressed a single KIR isoform. All NK-GLL showed a distinctive, abnormal immunophenotype. Four NK-GLL expressed a single KIR isoform; the remaining seven patients lacked all tested KIRs, which is also a distinct, abnormal finding. Immunoperoxidase staining of bone marrow biopsy specimens from NK-GLL patients with antibodies to CD8, TIA-1 and granzyme B revealed the disease-specific distinctive staining patterns previously found in T-GLL. These studies delineate the unique immunophenotypic features diagnostic of T-GLL and provide strong evidence that NK-GLL, like T-GLL, represents a clonal lymphoproliferative disorder.
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PMID:Demonstration of aberrant T-cell and natural killer-cell antigen expression in all cases of granular lymphocytic leukaemia. 1264 73

Apoptosis in response to granzyme B involves activation of caspase-dependent target cell death pathways. Herein, we show that granzyme B initiates caspase processing but cannot fully process procaspase-3 in intact Jurkat T leukemia or NT2 neuronal cells. Rather, the release from mitochondria of proapoptotic mediators cytochrome c, Smac/Diablo, and HtrA2/Omi facilitates full activation of caspases that results from autoprocessing. Bcl-2 overexpression in mitochondria suppresses the release of these proapoptotic molecules, resulting in cell survival despite partial procaspase processing by granzyme B. We propose that binding of inhibitor of apoptosis (IAP) proteins to partially processed procaspases inhibits cell death unless mitochondrial disruption also occurs in response to granzyme B or activated BH3-domain proteins such as truncated Bid.
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PMID:Caspase activation by granzyme B is indirect, and caspase autoprocessing requires the release of proapoptotic mitochondrial factors. 1264 50

Large granular lymphocyte (LGL) leukemia is a well-recognized disease of mature T-CD8(+) or less frequently natural killer cells; in contrast, monoclonal expansions of CD4(+) T-LGL have only been sporadically reported in the literature. In the present article we have explored throughout a period of 56 months the incidence of monoclonal expansions of CD4(+) T-LGL in a population of 2.2 million inhabitants and analyzed the immunophenotype and the pattern of cytokine production of clonal CD4(+) T cells of a series of 34 consecutive cases. Like CD8(+) T-LGL leukemias, CD4(+) T-LGL leukemia patients have an indolent disease; however, in contrast to CD8(+) T-LGL leukemias, they do not show cytopenias and autoimmune phenomena and they frequently have associated neoplasias, which is usually determining the clinical course of the disease. Monoclonal CD4(+) T-LGLshowed expression of TCRalphabeta, variable levels of CD8 (CD8(-/+dim)) and a homogeneous typical cytotoxic (granzyme B(+), CD56(+), CD57(+), CD11b(+/-)) and activated/memory T cell (CD2(+bright), CD7(-/+dim), CD11a(+bright), CD28(-), CD62L(-) HLA-DR(+)) immunophenotype. In addition, they exhibited a Th1 pattern of cytokine production [interferon-gamma(++), tumor necrosis factor-alpha(++), interleukin (IL-2)(-/+), IL-4(-), IL-10(-), IL-13(-)]. Phenotypic analysis of the TCR-Vbeta repertoire revealed large monoclonal TCR-Vbeta expansions; only a restricted number of TCR-Vbeta families were represented in the 34 cases analyzed. These findings suggest that monoclonal TCRalphabeta(+)/CD4(+)/NKa(+)/CD8(-/+dim) T-LGL represent a subgroup of monoclonal LGL lymphoproliferative disorders different from both CD8(+) T-LGL and natural killer cell-type LGL leukemias. Longer follow-up periods are necessary to determine the exact significance of this clonal disorder.
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PMID:TCRalphabeta+/CD4+ large granular lymphocytosis: a new clonal T-cell lymphoproliferative disorder. 1287 95


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