Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0029713 (immaturity)
 4,335 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The current hypothesis for the pathogenesis of myelofibrosis involves the intramedullary release of growth factors from defective or abnormal megakaryocytes. We describe a case of an acute micromegakaryocytic leukaemia, in a patient with chronic myelofibrosis, that provides additional evidence for this concept. The micromegakaryocytes, which reached 223 x 10(9)/l, were characterized morphologically by both light and electron microscopy, immunocytochemically and by platelet peroxidase activity. The cells were shown to have a mature cytoplasm, containing alpha granules and the associated proteins; vWF:Ag, fibrinogen, fibronectin and protein S. DNA analysis, by both a Seescan Solitaire Plus image analysis system and flow cytometry, revealed nuclear immaturity, with 92% of cells being diploid. Serum markers of connective tissue synthesis, namely carboxy terminal peptide of procollagen I (PICP), procollagen terminal peptide III (PIIIP) and laminin all increased significantly following transformation and were associated with an increase in platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta). These observations support the current hypothesis for bone marrow fibrosis formation and provide, for the first time, a link between in vivo growth factor release, bone marrow stromal turnover and megakaryocyte mass. In addition, the release of biologically active TGF-beta may explain both the increased fibronectin and angiogenesis characteristic of myelofibrotic bone marrow.
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PMID:Characterization of an acute micromegakaryocytic leukaemia: evidence for the pathogenesis of myelofibrosis. 843 38

The susceptibility of neonates to virus-induced disease is thought to reflect, in part, the immaturity of their immune systems. However, inoculation of newborn mice with low doses of Cas-Br-M murine leukemia virus induced a protective cytotoxic T lymphocyte (CTL) response. The inability of neonates to develop a CTL response to high doses of virus was not the result of immunological immaturity but correlated with the induction of a nonprotective type 2 cytokine response. Thus, the initial viral dose is critical in the development of protective immunity in newborns.
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PMID:Induction of protective CTL responses in newborn mice by a murine retrovirus. 870 18

Eighty six of 430 acute myeloblastic leukemia (AML) patients (20.0%) and forty of 173 acute lymphoblastic leukemia (ALL) patients (23.1%) had CD7 on their leukemia cells. CD7(+) AML occurred at a younger age than CD7(-) AML, and is more frequent in males. Hepatomegaly and central nervous system involvement were also more frequent in CD7(+) AML than in CD7(-) AML. The age of onset of CD7(+) ALL is also younger than that of CD7(-) ALL. Phenotypically, CD(+) AML expressed CD34, HLA-DR, and TdT more frequently than CD7(-) AML while CD7(+) ALL expressed CD13/33 more often than CD7(-) ALL cells responded most significantly to interleukin 3 (IL-3), whereas most CD7(-) AML cells responded more significantly to granulocyte macrophage-colony stimulating factor (GM-CSF) and/or granulocyte (G)-CSF than to IL-3. CD7(+)sCD3(-)CD4(-)CD8(-) ALL expressed G-CSF receptor and c-kit mRNA more frequently, which is not usual in other types of ALL. P-glycoprotein (P-gp)/multi-drug resistance gene (MDR1), thought to be expressed in hematopoietic stem cells, is expressed in CD7(+) AML and CD7(+)sCD3(-) CD4(-)CD8(-) ALL significantly more often than in CD7(-) acute leukemias and the CR rate and overall survival of CD7(+)AML was worse than CD7(-) AML. These data, collectively, suggest the close association of CD7(+) AML and CD7(+)sCD3(-)CD4(-)CD8(-) ALL, not only the common expression of CD7 itself but also because their phenotypical immaturity, cytokine receptor expression, P-gp/MDR1 expression and clinical manifestations including the frequent occurrence in males and the poor prognosis. We propose that CD7(+) acute leukemia is an hematopoietic stem cell leukemia which may be separate entity.
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PMID:Biological characteristics of CD7(+) acute leukemia. 872 5

Umbilical cord blood (UCB) is an attractive potential alternative to bone marrow (BM) as a source of hematopoietic progenitor cells since the number of progenitors in UCB is similar or even greater than that in normal BM. It was the aim of the present study to analyze the degree of immaturity of UCB progenitor cells. UCB mononuclear (MNC) and/or CD34+ cells were tested for surface antigen phenotype, expression of cytokines receptor, effect of stem cell factor (SCF) on colony growth, resistance to mafosfamide and replating potential. We have found that 34.9 +/- 3.4% and 77.9 +/- 2.6% of UCB CD34+ cells did not express CD38 and CD45RA antigens, respectively, suggesting that UCB contains a high proportion of immature progenitor cells. By means of three-color analysis, the receptor for SCF was detected on the majority of the CD34+ HLA-DR+ subpopulation; in fact, 81.8% +/- 4.3% of CD34+ HLA-DR+ cells were defined as SCF(low) and 8.1 +/- 1.5% as SCF(high). Colony growth of MNC and CD34+ cells was enhanced by the addition of SCF to methylcellulose mixture, resulting in a statistically significant increase in CFU-GM and CFU-GEMM but not in BFU-E numbers. UCB progenitor cells showed a higher resistance to mafosfamide treatment, in comparison to BM; the addition of SCF to the culture medium resulted in a statistically significant increase in mafosfamide concentration required to inhibit 95% of colony growth (P < or = 0.05). Moreover, as shown by single colony transfer assays, the presence of SCF in primary cultures promoted a significantly higher replating potential for both untreated (42 +/- 3.3% vs 21 +/- 4.6%, P < or = 0.018) and mafosfamide-treated samples (62 +/- 5.6% vs 44 +/- 6.1%, P < or = 0.018). In conclusion, UCB is a source of progenitor cells with immature characteristics in terms of surface antigen expression, distribution of SCF receptor, resistance to mafosfamide and replating potential. Therefore, UCB progenitor cells represent an ideal candidate population for experimental programs involving gene transfer and ex vivo stem cell expansion.
Leukemia 1997 Dec
PMID:Biologic and phenotypic analysis of early hematopoietic progenitor cells in umbilical cord blood. 944 33

While assessing the prognostic implications of immunophenotyping in 382 patients enrolled in treatment protocols of the Eastern Cooperative Oncology Group (ECOG) for de novo adult acute myeloid leukaemia, we identified 95 patients with a unique antigen profile characterized by high expression of the leucocyte integrin CD11b (CD11b+ AML). High expression of CD11b was defined as > or = 32% positive blasts based on the retrospectively established prognostic cut-off point for this antigen. Although CD11b is normally expressed by mature monocytes, natural killer cells and granulocytes, leukaemic blasts in CD11b+ AML lacked other immunologic monocytic features (e.g. CD14 and CD122, the interleukin-2 receptor beta chain) and demonstrated a high degree of immaturity, as reflected by a high incidence of blasts expressing the stem cell factor receptor, CD117, and few blasts positive for the myeloid differentiation antigen CD15. Furthermore, by FAB criteria, only 41% of CD11b+ AML cases were classified as M4/M5. Patients with CD11b+ AML had a low response rate (54%) when compared with acute monocytic leukaemia (AMOL; 82%, P = 0.006) or AML overall (68%, P = 0.031), independent of age, cytogenetic abnormalities and P-glycoprotein expression. Because of its poor prognosis, recognition of CD11b+ AML is clinically warranted and, given its morphologic and cytogenetic ambiguity, must be based on the unique antigen profile.
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PMID:Acute myeloid leukaemia expressing the leucocyte integrin CD11b-a new leukaemic syndrome with poor prognosis: result of an ECOG database analysis. Eastern Cooperative Oncology Group. 948 12

This study reports the immunophenotypic features of a series of 62 selected acute leukemia patients with increased incidence of argyrophilic proteins (AgNORs) at the time of initial diagnosis. Peripheral blood and bone marrow cells of patients with T-ALL, B-precursor ALL and AML were studied. The method of silver staining was used to determine the number of AgNORs per cell. Cell surface markers were detected by a standard immunofluorescence assay. To demonstrate the relationship between AgNOR quantity and cell proliferation, the expression of activation and proliferation antigens CD38 and CD71 was investigated. To characterize the immunophenotype and the discrete stages of differentiation, the wide panel of antibodies against lymphoid, myeloid and non-lineage specific antigens was used. The number of AgNORs at diagnosis ranged from 3.05 to 6.70. Immunophenotypic analysis showed a variation in CD38 and CD71 expression among different leukemia subtypes. CD71 antigen was more expressed in T-ALL than in B-precursor ALL or in AML. Notable was the relationship between increased AgNOR quantity and antigens that characterize the immaturity of leukemic cells. The association with CD7, CD2, CD5 (without CD3 membrane expression) and CD34 in T blasts was evident. High positivity of CD19, CD10, CD34 and HLA-DR in relation to the increased amount of AgNORs in B-lineage ALL was observed. The vast majority of AML patients with high numbers of AgNORs simultaneously expressed CD13, CD33, CD34 and HLA-DR. One third of AML cases coexpressed T cell marker CD7. In conclusion, the presence of increased numbers of AgNORs at diagnosis might reflect the dependence on an early stage of leukemia cell differentiation.
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PMID:The relationship between argyrophilic proteins and some immunophenotypic markers in acute leukemia cells. 960 7

Interleukin 12 (IL-12) is a pleiotropic cytokine and mediates several biological activities on human T and natural killer (NK) cells, including induction of IFN-gamma production, enhancement of cell-mediated cytotoxicity and comitogenic effects on resting T-cells. The major cellular sources producing IL-12 are antigen-stimulated monocytes, macrophages, and B-cells isolated from peripheral blood mononuclear cells (PBMC). Our laboratory has investigated the regulation of IL-12 gene expression in both cord blood and adult PBMC, and the effects of IL-12 on induction of IFN-gamma production, NK, and lymphokine-activated killer (LAK) cytotoxicity. IL-12 mRNA expression and protein production in LPS-stimulated cord blood MNC were 3-4 fold decreased when compared with adult PBMC. There were no differences between cord blood and adult PBMC in both basal levels of transcription or the degree of transcriptional activation of the IL-12 gene. Additionally, the half-life of IL-12 p40 mRNA was 3-fold lower in activated cord blood compared to adult PBMC. Exogenous IL-12 induced a significant increase of IFN-gamma from both cord and adult PBMC. Cord MNC has significantly reduced levels of NK activity, and IL-12 significantly enhanced cord blood NK cytotoxicity up to similar levels in adult PBMC. IL-12 also significantly enhanced cord blood NK and LAK activities against a broad range of neuroblastoma, leukemia, and lymphoma cell lines. Lower doses of IL-12 and IL-15 concomitantly generated either synergistic or additive effects on cord blood NK and LAK cytotoxicities. In light of the important biological functions of IL-12, reduced expression and production of IL-12 from activated cord blood may contribute to the immaturity of cord blood cellular immunity and contribute, in part, to decreased severe graft vs. host disease following unrelated cord blood stem cell transplantation. IL-12 enhancement of IFN-gamma, NK, and LAK activity in activated cord blood MNC up to comparable levels in adult PBMC suggests that exogenous IL-12 stimulation can compensate for the immaturity in cord blood cellular immunity. These characteristics of IL-12 biological activity strongly suggest its potential usefulness in future cancer immunotherapy.
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PMID:The regulation and biological activity of interleukin 12. 964 57

Thy-1 (CDw90) is a phosphatidylinositol-anchored protein, and is expressed on human pluripotential hematopoietic stem cells. The expression pattern of this antigen on leukemia cells is still controversial. In this study, 72 adult patients with pre-B cell acute lymphoblastic leukemia (pre-B ALL) were examined for the expression pattern of Thy-1 by using indirect immunofluorescence and reversed transcription polymerase chain reaction (RT-PCR) methods. Twelve cases were judged positive on the basis of conventional immunophenotype criteria. Thirteen cases showed a weak clonal shift on the fluorogram, even though their positive percentages were from 6.7% to 14.9%. Thy-1 gene transcripts were detected in all of the 13 cases showing a weak clonal shift. The study of antibody binding capacity, which was calculated by the mean fluorescence intensity of the test sample on the basis of a calibration curve using standard beads, showed that cases with more than 150 sites/cell could be positive. Thy-1 positivity in pre-B ALL was not associated with the expression of B-cell differentiation antigens. Thy-1 expression was significantly higher in pre-B ALL cases with karyotypic abnormalities than in those with normal karyotype (p = 0.0071). The t(9;22) abnormality was found in 18 of the 25 Thy-1+ cases. Simultaneous expression of transcriptional factors, GATA-2 and SCL, was frequently detected in the Thy-1+ cases. bcr-abl and GATA-2 are thought to play important roles in the proliferation of immature hematopoietic cells. Indeed, cell-cycle analysis showed that the cell population in the S/G2/M phase of the present Thy-1+ cases was less than that in the Thy-1- cases (p = 0.001770). Our data suggest that Thy-1 expression indicates the proliferative status of the leukemia cells, not their phenotypic immaturity.
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PMID:Frequent expression of human Thy-1 antigen on pre-B cell acute lymphoblastic leukemia with t(9;22). 969 10

We previously used peripheral newborn blood (NBB) as a possible in vivo experimental model for cord blood (CB) transplantation and showed that B10.D2 NBB cells successfully reconstituted adult (DBA/2 x B10.D2)F1 mice without causing graft-versus-host disease (GVHD), probably because of their phenotypic and functional immaturity. Here we investigated the influence of T-cell maturation occurring in NBB cells during the early postbirth period on the degree of engraftment, the incidence of GVHD, and the graft-versus-leukemia (GVL) potential. These parameters were compared in recipients grafted with bone marrow (BM) cells. We observed an increased percentage of CD4(+) mature T cells accompanied by the acquisition of proliferative responses to phytohemagglutinin (PHA) and to allogeneic cells of day-5 NBB cells. The capacity of day-2 NBB to engraft was moderately reduced and recipients developing GVHD were occasionally observed after the graft of day-5 NBB cells. No GVL effect was evidenced regardless of the time of postbirth blood collection. However, the GVL effect can be obtained by the delayed infusion of donor mature T cells to recipients grafted with day-0 NBB, without causing GVHD. In contrast, the same protocol applied to mice grafted with BM cells induced GVHD mortality of all recipients. Interleukin (IL)-10 but not IL-2 messenger RNA was expressed in NBB cells as opposed to BM cells. These findings suggest that, in terms of GVHD incidence, delayed infusion of mature T cells as post-transplant tumor immunotherapy would be more effective when applied after CB than after BM transplantation.
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PMID:Graft-versus-host disease and graft-versus-leukemia effect in mice grafted with peripheral newborn blood. 980 91

Background: Hairy cell leukemia (HCL) is a slowly progressive lymphoproliferative disorder that tends to afflict middle-aged adults, especially men. Blastic transformation of this form of leukemia is extremely rare. To date, a single case has been reported. Methods and Results: A case of HCL, evolving with blastic transformation after a 9- year clinical course, is reported. Routine histology, cytochemistry, flow cytometry immunophenotyping, and Southern blot analysis for B- and T-cell gene rearrangements were used in the evaluation. Although morphology at the time of presentation was characteristic of HCL, the cells were initially tartrate-resistant acid phosphatase (TRAP) negative. During a clinical course over several years, the hairy cells became progressively TRAP positive. The morphology of the leukemic cells changed 9 years after initial diagnosis, with blastic transformation and retaining strong TRAP positivity. Immunophenotypic analysis showed evolution from a characteristic hairy cell leukemic phenotype to a phenotype indicative of marked immaturity. Genotypic analysis showed an evolving pattern of immunoglobulin gene rearrangements, paralleling the morphology and phenotypic evolution and ruling out a second B-cell malignancy. Conclusions: This case report of blastic transformation in a patient with HCL is only the second such case identified in the medical literature to date.
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PMID:Blastic Transformation in a Case of Hairy Cell Leukemia. 1008 74


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