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

Retroviral gene transfer into hematopoietic cells has many experimental as well as clinical applications. Although transduction efficiency of retroviral vectors is higher than with conventional methods, selection of successfully transduced cells may become mandatory for efficient in vivo transfer. We have been evaluating a retroviral construct that meets the criteria for a clinically acceptable selection system. The Ser31 dihydrofolate reductase (DHFR) mutant confers resistance to methotrexate (MTX) due to decreased binding of the drug. while its enzymatic activity remains adequate for normal folate metabolism. Transduction of this vector into murine hematopoietic cells has been recently described and increase in MTX resistance could be observed. We investigated transduction of CD34-antigen positive subpopulations of hematopoietic progenitor cells and CD34-positive/CD38-negative subpopulations enriched for stem cells. We focused on two sources of primary hematopoietic cells, umbilical cord blood (UCB) and peripheral blood (PB) harvested from patients after mobilization with chemotherapy and/or cytokines. Both contain a large number of lineage restricted and pluripotent progenitor cells and can be expanded extensively ex vivo. Potential clinical applications of gene therapy in such cell populations include correction of inborn enzymatic diseases and support of high-dose chemotherapy by transplanting ex vivo transduced progenitor cells rendered more resistant to cytotoxic drugs. The feasibility and efficiency of retroviral transduction into UCB and PB has been reported recently.
Leukemia 1995 Oct
PMID:Increased resistance to methotrexate in human hematopoietic cells after gene transfer of the Ser31 DHFR mutant. 747 10

Most human acute myeloid leukaemia (AML) cells have limited proliferative capacity, suggesting that the leukaemic clone may be maintained by a rare population of stem cells. This putative leukaemic stem cell has not been characterized because the available in vitro assays can only detect progenitors with limited proliferative and replating potential. We have now identified an AML-initiating cell by transplantation into severe combined immune-deficient (SCID) mice. These cells homed to the bone marrow and proliferated extensively in response to in vivo cytokine treatment, resulting in a pattern of dissemination and leukaemic cell morphology similar to that seen in the original patients. Limiting dilution analysis showed that the frequency of these leukaemia-initiating cells in the peripheral blood of AML patients was one engraftment unit in 250,000 cells. We fractionated AML cells on the basis of cell-surface-marker expression and found that the leukaemia-initiating cells that could engraft SCID mice to produce large numbers of colony-forming progenitors were CD34+ CD38-; however, the CD34+ CD38+ and CD34- fractions contained no cells with these properties. This in vivo model replicates many aspects of human AML and defines a new leukaemia-initiating cell which is less mature than colony-forming cells.
 ...
PMID:A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. 750 44

We previously demonstrated that TGF-beta 1 antisense oligodeoxynucleotides can release early CD34+ bone marrow progenitors from quiescence, and increase the numbers of mixed and large erythroid colonies. As Steel Factor (SF) has a similar effect on colony formation by CD34+ cells, we tested whether this factor acts by blocking the inhibitory effects of TGF-beta. That this is not generally the case was demonstrated by the finding that the combination of TGF-beta 1 antisense with SF in cultures of CD34+ bone marrow cells yielded enhanced colony formation that was more than additive when compared to cultures containing the single agents. This combination also yielded enhanced colony formation by CD34+ umbilical cord blood cells, but in this case, the effect was slightly less than additive. Thus in cord blood, some, but not all, of the progenitors that are maintained in quiescence by TGF-beta can be triggered into cycle by SF. However, the absolute number of CFU-GEMMs found in the antisense TGF-beta plus SF cultures of cord blood was 4-fold higher than that found in comparable bone marrow cultures. These data correlate well with our previous observations that umbilical cord blood contains 4-fold more CD34+ CD38- cells, the population found to respond to TGF-beta 1 antisense oligodeoxynucleotides.
Leukemia 1994 Mar
PMID:Additive effects of steel factor and antisense TGF-beta 1 oligodeoxynucleotide on CD34+ hematopoietic progenitor cells. 751 Mar 56

Acute leukemia cells express myeloid, B-lymphoid and T-lymphoid lineage specific antigens. Many acute leukemias express the hematopoietic progenitor cell antigen CD34. Three proposed models of the normal human hematopoietic stem cell include CD34+ Thy-1low Lin-, CD34+ CD38-, and CD34+ HLA-DR-. The patterns of expression of CD34, Thy-1, CD38, HLA-DR, and multiple lineage-specific antigens on 49 consecutive pediatric B-cell precursor acute lymphoblastic leukemia (ALL) cases submitted for immunophenotyping (36 at first diagnosis, 13 at relapse) were analyzed. CD34+ expression was observed in 67% of the cases. CD34+ expression correlated with Thy-1low expression and expression of myeloid antigens (p < 0.001 and < 0.025, respectively). The CD34+ Thy-1low phenotype was observed in 65% of the cases; the CD34+ CD38- or CD34+ HLA-DR- phenotypes were observed in only three cases. Examples of heterogeneous expression of CD34 and Thy-1 were found in six cases, but CD38 expression was always bright and homogeneous in all positive cases. The data from this analysis indicates that the CD34+ CD38- or CD34+ HLA-DR- phenotypes would be more useful than the CD34+ Thy-1low phenotype for distinguishing normal hematopoietic stem cells from leukemic cells in childhood B-cell precursor ALL.
Leukemia 1994 Nov
PMID:Immunophenotypic differences between putative hematopoietic stem cells and childhood B-cell precursor acute lymphoblastic leukemia cells. 752 89

A new human monoclonal plasma cell line, designated UTMC-2, was established from the pleural effusion of a patient with immunoglobulin (Ig)A kappa-related multiple myeloma. The cultured cells were Epstein-Barr virus-negative and exhibited the morphological and ultrastructural features characteristic of plasma cells. Immunohistochemical analyses revealed the presence of cytoplasmic IgA kappa as well as the plasma cell-associated surface antigens CD38 and CD56. Other B-cell markers, including CD10, CD19, CD20, and HLA-DR, were absent. The UTMC-2 cells were interleukin (IL)-6 responsive: Co-culture with IL-6 increased IgA kappa synthesis and cell proliferation in a dose-dependent manner. In contrast, an IL-6 antisense oligonucleotide had an opposite effect. Although the UTMC-2 cells expressed IL-6 mRNA (as demonstrated by reverse transcriptase-polymerase chain reaction (RT-PCR)) and contained IL-6, the concentration of this cytokine in cell culture supernatants was less than that detectable by the enzyme-linked immunosorbent assay (ELISA) employed (i.e. <3 pg/ml). Further, cell growth was not inhibited by polyclonal or monoclonal anti-IL-6 antibodies. Flow cytometric analysis revealed that IL-6 receptors present on the surface of the UTMC-2 cells were not saturated with endogenous IL-6. Taken together, these results indicate that, in this human plasma cell line, IL-6 functions uniquely in an intracellular autocrine fashion to enhance Ig synthesis and cell growth. In this respect, the UTMC-2 cells represent a novel resource for further study of the role of IL-6 in the pathogenesis of multiple myeloma.
Leukemia 1994 Dec
PMID:Characterization of a novel interleukin-6 autocrine-dependent human plasma cell line. 752 62

CTLs bearing certain T-cell receptor V beta-regions are directed by the bacterial superantigen Staphylococcus enterotoxin A (SEA) to lyse MHC class II-positive cells. In order to extend superantigen-dependent cytotoxicity to MHC class II-negative carcinoma cells, covalent conjugates of superantigen and mAbs against surface markers of these cells have been used. We now describe a novel strategy which allows rapid selection of mAb suitable for superantigen targeting against MHC class II-negative tumor cells. A recombinant fusion protein of protein A and SEA binding to the mAbs CD7 or CD38 was able to mediate T cell-dependent lysis of MHC class II-negative Molt-4 and CCRF-CEM acute lymphatic leukemia cell lines. Lysis was dose dependent and correlated with E:T cell ratio. In contrast, SEA alone did not induce any significant lysis. In order to decrease the MHC class II affinity of the protein A-SEA complex, a point mutation was introduced into SEA (protein A-SEA mu9). The mutated fusion protein had similar potency as protein A-SEA against Molt-4 cells but was 100-fold less active against MHC class II-positive cells. Considering the efficiency and specificity of the mutated SEA protein interacting with mAb in targeting T lymphocytes against MHC class II-negative leukemia cells while only marginally affecting normal MHC class II-positive cells, we suggest the development of SEA-mAb fusion proteins as a potential adjuvant therapy of leukemias.
 ...
PMID:Antibody-targeted superantigens induce lysis of major histocompatibility complex class II-negative T-cell leukemia lines. 753 May 98

Peripheral blood cells from a female patient with Ph1-positive chronic myelogenous leukemia (CML) in blast crisis were serially transplanted in BALB/c nude mice for 16 passages. This in vivo cell line, designated CML-N-1, had Ph1 chromosome abnormality and BCR gene rearrangement. The cells expressed CD11b, CD13, CD33, CD34, CD38, and HLA-DR antigens until the 11th passage and subcutaneous tumors produced by these passages were composed of admixtures of immature and maturing cells that differentiated to basophils when cultured in vitro. From the 12th passage on, the tumors became composed mainly of immature cells expressing CD13, CD34, and HLA-DR, and no longer differentiated to basophils even upon in vitro culture. In contrast to the vigorous proliferation in vivo, CML-N-1 cells from any passage failed to proliferate in vitro under standard liquid culture conditions with or without growth factors, such as granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, monocyte colony-stimulating factor, interleukin 3, interleukin 6 and stem cell factor. However, a continuously growing cell line, designated CML-C-1, was established by culturing CML-N-1 cells on feeder layers of mouse bone marrow stromal cells. This mouse bone marrow stromal cell-dependent cell line showed immature cell morphology and expressed early myeloid phenotype positive for CD13, CD34, and HLA-DR. These results indicate that mouse bone marrow stromal cells provide a certain growth factor(s) active on human leukemia cells.
 ...
PMID:Direct transplantation of chronic myelogenous leukemia cells into nude mice and establishment of a leukemic stem cell (Ph1+, CD34+) line dependent on mouse bone marrow stromal cells in vitro. 754 Jun 8

Antigen CD34 and other markers of cell membrane were investigated in cells from 43 patients with primary acute nonlymphoblastic leukemia (ANLL) by immunofluorescence test. The blast cells of 13 patients (30.2%) expressed antigen CD34. The patients with positive CD34 were no significantly different from the remaining 30 patients with negative CD34 with respect to age, serum lactate dehydrogenase (LDH), hemoglobin, white blood cell count, platelet count and the proportion of blast cells in blood and bone marrow, but their blasts were more likely to express HLA-DR, CD38, CD7 and lack of CD15 antigen. These patients had FAB M1 or M5a morphologic characteristics and lower complete remission (CR) rate. This result demonstrated that CD34 positive ANLL is poorly differentiated.
 ...
PMID:[Clinical and immunophenotyping features of CD34-positive acute nonlymphoblastic leukemia]. 754 28

Leukemia may be viewed as a clonal expansion of blast cells; however, the role of primitive cells and/or stem cells in disease etiology and progression is unclear. We investigated stem cell involvement in leukemia using fluorescence in situ hybridization (FISH), immunofluorescence labeling of hematopoietic subpopulations, and flow cytometric analysis/sorting to discriminate and quantify cytogenetically aberrant stem cells in 12 acute myeloid leukemia (AML) and three myelodysplastic (MDS) specimens. Flow cytometric analysis and sorting were used to discriminate and collect a primitive subpopulation enriched in stem cells expressing CD34+ and lacking CD33 and CD38 (CD34+lin-). A subpopulation containing progenitors and differentiating myeloid cells expressed CD34, CD33, and CD38 (CD34+lin+). Nine specimens contained less than 10% CD34+ cells and, thus, were considered to be CD34- leukemias. Mature lymphoid, myeloid, and erythroid subpopulations were sorted on the basis of antigen-linked immunofluorescence. Cytogenetically aberrant cells in sorted subpopulations were identified using FISH with enumerator probes selected on the basis of diagnosis karyotype. Cytogenetically aberrant CD34+lin- cells were present at frequencies between 9% and 99% in all specimens. CD34+lin- cytogenetically aberrant cells comprised between 0.05% and 11.9% of the marrow/blood specimens. Cytogenetically aberrant CD34+lin+ cells constituted 0.01% tp 56% of the marrow/blood population. These data demonstrate that aberrant cells are present in primitive CD34+ stem cell compartments, even in CD34- leukemias. Stem cell involvement was confirmed further by sorting lymphoid and erythroid subpopulations from eight specimens in which the predominant leukemic population lacked lymphoid/erythroid differentiation markers. In these specimens, as well as in multiple lineages, suggests involvement of a cell(s) with multilineage capabilities. The ability of aberrant CD34+lin- stem cells to contribute to clonal and compartment expansion within immunofluorescently defined subpopulations was evaluated to explore the functional phenotype of aberrant CD34+lin- cells. Analysis of compartment size and aberrant cell frequency suggests that frequency of cytogenetically aberrant stem cells is uncoupled from compartment size. These data suggest that cytogenetically aberrant cells in the primitive compartment show varying abilities to expand primitive compartments. Cytogenetically aberrant CD34+lin- cells precede the blast subpopulation in hierarchical maturation and may in some cases by considered preleukemic, requiring maturation or additional mutations before transformation (eg, compartmental expansion) occurs.
 ...
PMID:Cytogenetically aberrant cells in the stem cell compartment (CD34+lin-) in acute myeloid leukemia. 754 97

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.
 ...
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


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>