Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CD19+ CD38+ human Burkitt's lymphoma cell line Ramos grows aggressively when injected intravenously (i.v.) into severe combined immunodeficient (SCID) mice, killing 100% of animals within a 33-42 day period with widely disseminated disease. Treatment commencing 7 days after i.v. injection of Ramos cells, with 3 doses of an anti-CD19 immunotoxin (IT; BU12-SAPORIN) or an anti-CD38IT (OKT10-SAPORIN) led to a significant prolongation of survival compared with sham-treated controls; the anti-CD38 IT gave the greatest prolongation of survival, but all treated animals eventually succumbed to disease. When both ITs were used in combination at equivalent dose levels, the therapeutic outcome was significantly improved over that obtained for single IT therapy, with 20% of animals surviving disease-free to 300 days. When anti-CD38 IT was given in combination with anti-CD19 antibody there was no therapeutic improvement over anti-CD38 IT used alone. However, when anti-CD19 IT was given in combination with CD38 antibody, a significant prolongation of survival ensued over that obtained with anti-CD19 IT alone, though this was not as significantly pronounced as that obtained when both ITs were used in combination and was only as good as the survival obtained with OKT10 antibody used alone. CD19 and CD38 are expressed on the surface of the vast majority of B-cell lymphoma and common acute lymphoblastic leukaemia cells, and our findings provide a sound rationale for a combination immunotoxin trial in these diseases directed against both these target molecules.
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PMID:Therapy of human B-cell lymphoma bearing SCID mice is more effective with anti-CD19- and anti-CD38-saporin immunotoxins used in combination than with either immunotoxin used alone. 754 82

About half of the patients with follicular lymphoma will develop an aggressive B cell lymphoma with morphological changes in growth pattern and cellular morphology. Changes of the immunophenotype, especially of the expression of immunoglobulin (Ig) have been documented less frequently. Multiple tumor samples of two patients with follicular lymphoma who developed tumor progression, were studied by Southern blot analysis for rearrangements of the Ig genes and the oncogenes BCL2 and MYC. In both patients, the general pattern of Ig gene rearrangements, especially of the Ig light-chain genes, and the structure of the t(14;18) breakpoint as assessed by the polymerase chain reaction (PRC) and fine restriction mapping, remained unaltered with time. However, both within the functional Ig heavy-chain allele and around the t(14;18) breakpoint, extensive secondary alterations took place. This indicates clonal evolution rather than the appearance of an independent lymphoma. In the first case with progression from follicular lymphoma to Burkitt's lymphoma 3 years after diagnosis, alterations were especially present 3' of the t(14;18) breakpoint. In the second patient with a change from follicular to diffuse centroblastic lymphoma 4 years after diagnosis, subsequent class switches from IgM to IgG and to defective IgH expression were accompanied by deletion of C mu sequences and a rearrangement of the MYC gene, respectively. Additionally, in both patients alterations in individual restriction sites occurred, which most likely were due to somatic mutations within both the functional IgH and translocated allele. Our data indicate that complex alterations of both the functional and non-functional IgH allele may accompany tumor progression and may erroneously suggest the appearance of independent clones by Southern blot analysis. It remains to be established whether these alterations are causative events or the consequence of genetic instability and clonal evolution.
Leukemia 1995 Oct
PMID:Histological conversion of follicular lymphoma with structural alterations of t(14;18) and immunoglobin genes. 756 20

The high incidence of spontaneous T cell lymphomas in AKR mice (affected by sustained viremia) can be greatly reduced by experimental manipulations including thymus removal at young age or by genetic manipulation changing the Fv-1 allele that controls replication and spread of viruses (establishing the congenic AKR.Fv-1b mice). Although T cell lymphomagenesis is prevented, all these mice were shown to carry endogenous ecotropic provirus-induced potential lymphoma cells (PLCs) in a dormant state. The termination of the dormant state, leading to a high incidence of CD5+ IgM+ B cell lymphomas, was triggered by interference with T cell functions (optimal effect observed following in vivo administration of anti-CD8 moAb), administration of T cell growth factors or by injecting the MCF-247 recombinant virus isolate (from AKR origin) that affects T cell functions. The assumption that the PLC dormant state is maintained through specific immunological mechanisms (involving T cells or antibodies recognizing PLCs) could not be substantiated experimentally. The results of the present studies suggest that T cells provide immunoregulatory signals or factors that contribute to the maintenance of the B cell lymphoma arrest and/or proliferation. Analysis of cytokine levels produced by splenocytes taken from mice during PLC dormancy or its breakdown indicated reduced levels of IL-2 and IL-4 and marked elevation of IL-1 and IL-6 associated with the termination of the dormant state. The effect of IL-1 and IL-6 on terminating the dormant state was demonstrated by injecting these cytokines into PLC carriers, thymectomized 12-month-old AKR mice, yielding 80-85% CD5+ IgM+ B cell lymphomas. The role of IL-6 on B cell lymphoma proliferation was also indicated in MCF-247 mediated termination of dormancy, by inhibiting significantly its effect via in vivo administration of anti IL-6 moAbs.
Leukemia 1995 Jun
PMID:Role of cytokines in termination of the B cell lymphoma dormant state in AKR mice. 759 76

Protein tyrosine phosphorylation is known to play key roles in lymphocyte signal transduction, and phosphotyrosine phosphatases (PTP) can act as both positive and negative regulators of these lymphocyte signals. We sought to examine the role of PTP further in these processes by characterizing the effects of bis(maltolato)-oxovanadium(IV) (BMLOV), previously known to be a nontoxic insulin mimetic agent in vivo. BMLOV was found to be a potent phosphotyrosine phosphatase inhibitor. BMLOV induced cellular tyrosine phosphorylation in B cells in a pattern similar to that observed following antigen receptor stimulation, whereas little tyrosine phosphorylation was induced in T cells. In B cells, BMLOV treatment resulted in tyrosine phosphorylation of Syk and phospholipase C gamma 2, while sIgM-induced signals were inhibited. By contrast, T cell receptor signals were moderately increased by BMLOV, and the cells displayed greater induction of IL-2 receptor without toxicity. The compound selectively induced apoptosis in B cell lymphoma and myeloid leukemia cell lines, but not in T cell leukemia or colon carcinoma cells. Interleukin-4 plus anti-CD40 antibody treatment of normal human peripheral B cells rescued the cells from BMLOV-induced death. These results suggest that phosphotyrosine phosphatase inhibitors can activate B cell signal pathways in a lineage-specific manner, resulting in desensitization of receptor-mediated signaling and induction of apoptosis.
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PMID:Lineage-specific induction of B cell apoptosis and altered signal transduction by the phosphotyrosine phosphatase inhibitor bis(maltolato)oxovanadium(IV). 765 67

Tumor-infiltrating T-lymphocytes (T-TIL) are putative mediators of tumor containment that exhibit unique specificity for autologous tumor cells. The magnitude of T-TIL response in biopsy specimens from patients with B-cell lymphoma has been suggested as an independent predictor of clinical outcome. Since recognition of tumor antigens may occur in association with major histocompatibility complex (MHC) molecules, effective T-TIL tumor immunosurveillance may be limited by either failure to express MHC-encoded recognition structures and/or host T-cell immunocompetence. To further delineate T-cell immunoregulation in B-cell lymphoma, we assessed T-TIL fraction and tumor expression of invariant class I and class II HLA determinants by immunohistochemistry in biopsy specimens. Two distinct clinical cohorts of B-cell lymphoma were investigated to delineate pathogenetic differences in T-TIL response. One group, representing immunodeficient and transplant-related lymphomas, comprised 18 patients with AIDS- or allograft-related lymphoma. The second group comprised 83 consecutive cases of sporadic diffuse large cell (DLCL) lymphoma. Median CD8+ T-TIL was significantly lower (4.9% versus 12.7%) among immunodeficiency-associated lymphoma and the frequency of cases with low (< 6%) CD8+ T-TIL greater (76% versus 23%) (p < 0.0001). None of the immunodeficiency-associated lymphomas demonstrated non-polymorphic HLA loss. Absence of one or more class I or II HLA determinants was found in 13 out of 19 (68%) sporadic DLCL specimens with low CD8+ T-TIL, compared to 20% of cases with higher T-TIL fraction (p = 0.0004). These findings implicate impaired host immunosurveillance in deficient T-TIL response in immunodeficiency-associated B-cell lymphoma, whereas low T-TIL in sporadic cases of DLCL relates to tumor loss of HLA determinants. Strategies to modulate tumor HLA expression or augment antitumor response merit investigation in patients with B-cell lymphoma.
Leukemia 1993 Mar
PMID:Deficient tumor-infiltrating T-lymphocyte response in malignant lymphoma: relationship to HLA expression and host immunocompetence. 768 Apr

A novel immunocytochemical approach to the detection of cytoplasmic antigens, exemplified by immunoglobulin and CD3, was evaluated using benign and 155 malignant lymphohematopoietic cell specimens and conventional techniques for detailed comparison. It relies on (a) electrostatic cell attachment to poly-L-lysine-coated multispot slides, (b) sequential use of glutaraldehyde fixation and detergent permeabilization, and (c) staining of endogenous peroxidases and antigens in contrasting colors. Differential staining instead of inactivation of endogenous peroxidases and avoidance of artifacts incurred in conventional cytocentrifugation, dehydration, and alcohol or acetone fixation uniquely afforded improved precision in cell identification, clear distinction of cytoplasmic from surface antigenic staining, and greatly enhanced sensitivity in antigen detection, all combined with increased performance efficiency achieved by the use of multispot slides. With this method, cytoplasmic immunoglobulin and CD3 were found more widely distributed than has been previously recognized. Thus, almost all malignant cells in all cases of B-cell lymphoma/leukemia (encompassing the major subtypes) and T-ALL, as well as substantial proportions of benign mature B- and T-lymphocytes, stained strongly positive for cIg and cCD3, respectively, whereas myeloid cells were consistently negative. High sensitivity combined with excellent cytomorphology and differential myeloperoxidase staining permitted unequivocal differentiation of minute fractions of malignant cells against a heterogeneous background of benign cells.
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PMID:Optimized detection of cytoplasmic immunoglobulin and CD3 in benign and malignant lymphoid cells: enhanced sensitivity combined with differential staining of endogenous peroxidases and light microscopic morphology. 768 87

JD118 is a murine immunoglobulin M monoclonal antibody (mAb) under study as a therapeutic agent that is capable of potent human complement-mediated cytotoxicity (CMC) against B-cell lymphoma and leukemia targets. The JD118 antigen target was upregulated on fresh human B cells and B-cell neoplasms after brief in vitro incubation in media containing calf serum. To determine if cytokines could also lead to upregulation of JD118 antigen, alpha-interferon (alpha-IFN), gamma-interferon (gamma-IFN), interleukin 2 (IL-2), or IL-4 were added to fresh neoplastic B cells in serum-free media and changes in JD118 antigen expression were evaluated by flow cytometry (FCM). IL-4 was found to be the predominant cytokine responsible for inducing upregulation of the JD118 antigen. Marked JD118 upregulation by IL-4 was seen in 14 out of 14 chronic lymphocytic leukemia (CLL) samples tested, with 50 to 750-fold increases in four samples, 11 to 49-fold increases in four samples, and up to 10-fold increase in six samples. One B-cell lymphoma specimen was upregulated 18-fold, but no up-regulation was demonstrated in one hairy cell leukemia and two acute myelogenous leukemia specimens tested. The specificity of the IL-4 up-regulation was demonstrated by the elimination of its activity by blocking with a neutralizing anti-IL-4 mAb. IL-4 upregulation allows JD118 mAb CMC against otherwise antigen-negative targets and argues for phase I trials using a combination of IL-4 cytokine and mAb for B-cell neoplasms.
Leukemia 1993 Jul
PMID:Interleukin-4 priming enhances a target for human complement-mediated cytotoxicity of CLL. 768 3

Patients with B-cell chronic lymphocytic leukemia (CLL) infrequently may develop high-grade B-cell lymphoma, or Richter's syndrome lymphoma (RS lymphoma). Such lymphomas differ from the original leukemia in both histology and clinical behavior. Studies seeking to define the clonal relationship between the cells of the two malignancies in any one patient have yielded conflicting reports. We examined the clonal relationship between the early and late neoplastic cells of a patient who underwent Richter's transformation. In contrast to the original leukemia cells, the secondary high-grade lymphoma was CD5-. However, both the leukemia cells and the evolved RS lymphoma expressed surface IgM lambda reactive with Lc1, a murine monoclonal antibody specific for a supratypic cross-reactive idiotype encoded by a subset of human Ig variable region genes of the VH4 subgroup. Nucleic acid sequence analyses of the heavy and light chain variable region genes expressed by both leukemia and lymphoma cells show that the CD5- B-cell lymphoma constitutes a clonal expansion of mutant cells derived from the original CD5+ B-cell leukemia. Moreover, certain sets of somatic mutations distinguish the Ig variable region genes used by RS lymphoma from those expressed by the CLL B cells. This is the first study to establish the clonal relationship between CLL and RS lymphoma through primary structural analyses of the expressed Ig genes.
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PMID:Common clonal origin of chronic lymphocytic leukemia and high-grade lymphoma of Richter's syndrome. 769 38

We have analyzed the clinical and laboratory features of 42 patients with B-cell leukemia. Based on the FAB criteria, the cases were classified in 3 groups: I) typical CLL 15, II) atypical CLL 9 which included 6 cases with large cells, and III) B-cell lymphoma in leukemic phase 18. Cases diagnosed as typical CLL (group I) had similar features to those seen in CLL patients from Western countries. The morphology and markers in cases from group III corresponded to B-cell lymphoma in leukemic phase. On the other hand, group II included 3 cases classified as atypical CLL according to FAB criteria. 1 CLL/PL and 2 mixed CLL and 6 cases with rather distinct features, namely: 1) lymphocytosis (42 +/- 41 x 10(9)/l in average) with large mature-looking lymphocytes with abundant cytoplasm: 2) an immunological profile consistent with CLL but, in addition with the consistent expression of CD38; 3) absence of a monoclonal band in the serum and 4) a clinical course and prognosis similar to CLL. Our findings suggest the existence of a B-cell disorder in Japan very close to CLL but distinct from typical and atypical CLL as seen in Western countries. Further studies would clarify whether such an entity is exclusively confined to Japan having a distinct natural history.
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PMID:Morphological and immunophenotypical characterization of Japanese B-cell lymphocytic leukemia. 769 16

Five tumours, which arose in cats naturally or experimentally infected with feline immunodeficiency virus (FIV), were examined with molecular probes to establish tumour cell lineage and to screen for integrated viral sequences. Three of the tumours were classed as B-cell lymphomas on the basis of morphology, immunocytochemistry, rearrangement of immunoglobulin heavy chain genes and lack of rearrangement of T-cell receptor (TCR) beta-chain genes. Two of these B-cell tumours arose in specific pathogen-free (SPF) cats experimentally infected with FIV. One case of multi-centric lymphosarcoma came from a cat naturally infected with both FIV and feline leukaemia virus (FeLV). This tumour contained integrated FeLV proviral sequences and was judged to be of T-cell origin on the basis of TCR gene rearrangement. The fifth case was a mast cell tumour. Rearrangement of the c-myc locus was not found in any of the FIV-associated tumours but was shown to be present in a rare immunoblastic B-cell lymphoma which arose in an uninfected SPF cat. None of the FIV-associated tumours showed evidence of integrated FIV sequences by Southern blot hybridisation, despite isolation of infectious virus from in vitro cultures of tumour cells in I case. These results confirm that FIV-associated tumours can occur in the absence of FeLV and suggest that the role of FIV in lymphomagenesis is generally indirect.
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PMID:Molecular analysis of tumours from feline immunodeficiency virus (FIV)-infected cats: an indirect role for FIV? 770 53


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