Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Main indications for allogeneic bone marrow transplantation are severe aplastic anemia, severe combined immunodeficiency, acute leukemia and chronic myeloid leukemia. In standard risk situations survival rates are 50 to 80%. The probability of disease-free survival after bone marrow transplantation is depending on the stage of disease. If possible bone marrow transplantation should be performed early, not in advanced disease when conventional measures failed. Main problems are therapy-related organ toxicity, rejection, graft-versus-host disease and a long lasting risk of infection. Usually histocompatible relatives of the patients are selected as marrow donors. Bone marrow transplantation using unrelated donors is under investigation. Autologous transplantations with cryopreserved marrow are performed in acute leukemia, malignant lymphomas and some solid tumors, but prospective studies comparing transplantation and conventional therapeutic procedures are still missing.
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PMID:[Bone marrow transplantation. Overview and personal results]. 128 79

We analyzed the role of CD4+ and CD8+ T cells in H-2-disparate skin allograft rejection in the mutant mouse strain C.B-17/Icr scid with severe combined immunodeficiency. On the day of skin allografting, scid mice were adoptively transferred with negatively selected CD4+ or CD8+ splenocytes from normal unsensitized C.B-17/Icr mice. These populations were obtained using a double-mAb--plus--complement elimination protocol using anti-CD4 or anti-CD8 mAb that resulted in no detectable CD4+ or CD8+ cells by FACS and negligible numbers of cytolytic T lymphocytes by limiting dilution analysis in anti-CD8 treated populations. Spleen cells were removed from grafted mice at the time of rejection and were tested in vitro for antidonor reactivity in several assays: mixed lymphocyte culture, cell-mediated lympholysis, and LDA for CTL and for IL-2-producing HTL. The presence of Thy 1.2+, CD4+, or CD8+ cells was determined by FACS. All control C.B-17 mice and scid mice adoptively transferred with nondepleted CD4+, and CD8+ cells rejected skin allografts with similar mean survival times (15.6 +/- 1.5, 18.8 +/- 3.4, 18.0 +/- 5.4, respectively), whereas control scid mice retain skin allografts indefinitely (all greater than 100 days). C.B-17 syngeneic grafts survived indefinitely in all groups. At the time of rejection, splenocytes from scid mice receiving CD4+ cells had negligible donor-specific cytotoxicity in CML and negligible numbers of CTL by LDA, but demonstrated a good proliferative response in MLC and IL-2-producing cells by LDA (frequency = 1/1764). There were no detectable CD8+ cells present by FACS analysis. Conversely, splenocytes from scid mice adoptively transferred with CD8+ cells had strong donor-specific cytotoxicity in CML (58.8% +/- 16.1%) and CTL by LDA (frequency = 1/3448), but no significant proliferation was detected in MLC. There were no detectable CD4+ cells by FACS, but there were small numbers of IL-2-producing cells by LDA (frequency = 1/10,204). These data demonstrate that CD4+ cells adoptively transferred into scid mice are capable of mediating skin allograft rejection in the absence of any detectable CD8+ cells or significant functional cytolytic activity. The adoptive transfer of CD8+ cells also results in skin allograft rejection in the absence of detectable CD4+ cells. The detection of small numbers of IL-2 secreting cells in these mice may indicate that CD(8+)-mediated allograft rejection in this model is dependent on IL-2-secreting CD8+ cells.
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PMID:Mediation of skin allograft rejection in scid mice by CD4+ and CD8+ T cells. 135 12

Existing in vitro culture technology does not permit the routine propagation of most human myeloid leukemias. Previous work has shown the usefulness of mice with severe combined immunodeficiency (SCID) for the growth of human lymphoblastic leukemia. We show here that human myeloid cell lines and bone marrow samples from patients with acute myeloid leukemia (AML) and blast crisis of chronic myeloid leukemia (CML) also grow in SCID mice. Human AML or CML cell lines (three of three lines tested) grew in the bone marrow and peripheral blood of the mice after intravenous (IV) inoculation in a pattern closely resembling human AML. To define the best conditions for the growth of primary human myeloid leukemia cells, samples were transplanted into mice at several alternative sites. Using flow cytometry and Southern analysis, mice were analyzed at defined intervals up to 36 weeks after transplantation for the presence of human cells in various tissues. For four of four patients with AML and two of two patients with blast crisis of CML, myeloblasts grew locally at the site of implantation and were detected in the murine hematopoietic tissues. In contrast, marrow implants from patients in the chronic phase of CML (six patients) showed infrequent and limited myeloid growth in the mice. These findings demonstrate that the SCID mouse is a reproducible system for the propagation of blastic human myeloid leukemias. The differential growth of early- versus late-phase CML suggests that the SCID mouse may be a useful assay for identifying biologically aggressive leukemias early in their clinical presentation.
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PMID:Propagation of human blastic myeloid leukemias in the SCID mouse. 156 35

Adenosine deaminase (ADA) deficiency is associated with a fatal severe combined immunodeficiency. Because most patients do not have a suitable marrow donor, the introduction of a normal ADA gene into the patient's marrow cells is a potentially useful alternative therapy. To identify vectors that provide optimal gene expression in human hematopoietic cells, we investigated retroviral vectors containing the ADA gene under the transcriptional control of the promoter/enhancers of Moloney murine leukemia virus, the simian virus 40 early region, the cytomegalovirus immediate-early gene, the lymphotropic papovavirus, and the human beta-globin gene. ADA expression from these vectors was monitored in the ADA- human histiocytic lymphoma cell line DHL-9, and in the multipotential chronic myeloid leukemia cell line K562. ADA expression in infected K562 cells was also measured after induction of megakaryoblastic differentiation by phorbol ester, and after induction of erythroid differentiation by sodium n-butyrate or hemin. In these hematopoietic cell lines, the vectors that contained ADA controlled by either the Moloney murine leukemia virus promoter (LASN) or the cytomegalovirus promoter (LNCA) expressed ADA at much higher levels than the other vectors tested. Furthermore, in K562 cells infected with LASN and LNCA vectors, induction of terminal differentiation resulted in the same or higher level expression of ADA. These cell lines have permitted the evaluation of transduced gene expression in proliferating and differentiating hematopoietic cells that provide a model for bone marrow-targeted gene therapy.
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PMID:Expression of human adenosine deaminase from various strong promoters after gene transfer into human hematopoietic cell lines. 275 48

Cell substitution in the form of "tailored haemotherapy " should be an essential part of medical oncology at the present time. In the conventional therapy of solid tumors patients do not enter into prolonged phases of severe haemopoietic insufficiency. Accordingly platelet and granulocyte transfusions will be exceptional. It is mainly the red cell transfusion which plays the most important role. The possible complication of cell substitution should always be kept in mind. Here the risk of alloimmunisation which makes a continuation of transfusion therapy or a subsequent bone marrow transplantation problematic, is just one of the examples. Modern cell separation techniques allow the production of highly concentrated cell preparations aiming at the reduction of the frequency of transfusions and minimizing the risk of sensitisation. If rich concentrated preparations have to be given to immunodeficient patients an irradiation should proceed their transfusion, otherwise the immunocompetent lymphocytes contained in the preparations could induce graft versus host reactions. Allogenic bone marrow transplantation is more becoming the treatment of choice for severe combined immunodeficiency, severe aplastic anemia, acute myeloid leukemia, and chronic myeloid leukemia. At the present time the place of allogeneic or autologous bone marrow transplantation as a treatment of lymphomas and solid tumors is still unsettled.
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PMID:[Substitution of blood components]. 637 39

We have developed culture conditions for the efficient expansion of cytotoxic effector cells from peripheral blood mononuclear cells (PBMNCs) by the timed addition of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), and the monoclonal antibody (MoAb) OKT3. These cells, termed cytokine-induced killer (CIK) cells, are composed primarily of T cells, and the population of cells with the greatest cytotoxic activity is an otherwise rare population of CD3(+)CD56(+) cells that expand dramatically under these culture conditions. CIK cells were expanded from PBMNCs from 13 patients with chronic myeloid leukemia (CML). These cultures contained a variable number of T cells at the start of the culture (median 44%, range 1% to 64%), yet after 21 to 28 days of culture, virtually all of the cells were CD3(+) T cells (median 97%, range 90% to 99%). The CD3(+)CD56(+) subset of cells expanded significantly (median 25-fold, range 2.2- to 525-fold). CIK cells from all patients showed cytotoxicity against the tumor cell lines OCI-LY8 and K562. In four patients the expanded CIK cells suppressed colony growth of autologous CML blast cells and myeloid progenitor cells. Allogeneic CIK cells from normal donors also suppressed CML colony growth but did not inhibit growth of normal hematopoietic colonies. Twelve of the 13 cultures were exclusively composed of Philadelphia (Ph)-negative cells and one culture had 1 out of 20 Ph-positive metaphases after 4 weeks in culture. Intracellular cytokine production was assayed by fluorescence-activated cell sorter (FACS), and the expanded T-cell cultures produced IL-2, IFN-gamma, and tumor necrosis factor-alpha (TNF-alpha), but not IL-4. Both the CD4(+) and CD8(+) subsets secreted this cytokine profile. To test the in vivo activity of the expanded CIK cells, CML was engrafted into severe combined immunodeficiency disease (SCID) mice using matrigel. After 4 weeks, 4 x 10(7) autologous CIK cells were injected intravenously by tail vein injection into groups of mice, and the animals were sacrificed after a total of 18 weeks. Bcr-abl was detected in the bone marrow or spleen of 5 out of 6 control mice and only 2 out of 13 mice who received the autologous CIK cells (P = .02). In an additional series of animals, the mice did not engraft with CML but instead developed large human Epstein-Barr virus-associated lymphomas by 12 weeks. The mice who received autologous CIK cells at 4 weeks had either no tumor (5) or small tumors (5), whereas all 10 mice that received CIK cells at week 8 developed lymphomas; however, these were not as large as in the 10 control mice who did not receive CIK cells (P = . 03). This study shows that CIK cells, which are Ph chromosome-negative, can be expanded from patients with CML and have potent in vitro and in vivo efficacy against autologous tumor cells.
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PMID:Expansion of Philadelphia chromosome-negative CD3(+)CD56(+) cytotoxic cells from chronic myeloid leukemia patients: in vitro and in vivo efficacy in severe combined immunodeficiency disease mice. 978 69

Gene transfer is a potentially powerful tool for the treatment of a wide variety of diseases. The transfer of these genes is achieved by utilizing a variety of vectors, including retroviral, adenoviral, adeno-associated virus (AAV) and a number of non-viral mechanisms. Numerous studies have successfully demonstrated transduction of genes into target cells with a variety of vectors, and have provided 'proof-in-principle' that gene transfer can result in prolonged in vivo expression of transduced genes, albeit at low quantities. Furthermore, gene marking studies in acute myeloblastic leukemia (AML), chronic myeloid leukemia (CML) and neuroblastoma have elegantly demonstrated that gene-marked tumor cells contribute to relapse following autologous transplantation. However none of the studies examining the therapeutic benefit of gene therapy has definitively demonstrated a clinically meaningful benefit. Nonetheless, the results of studies involving gene transfer for severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), melanoma and lung cancer highlight the potential benefit of this strategy. This review will discuss mechanisms of achieving gene transfer into target cells. It will examine some of the pre-clinical and clinical results to date and will discuss some of the potential uses of gene transfer for therapeutic purposes.
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PMID:Gene transfer: a review of methods and applications. 983 7

Chronic myeloid leukemia (CML) is a clonal disorder of primitive hematopoietic stem cells characterized by a reciprocal translocation between chromosomes 9 and 22. Animal models of CML would be useful to study the biology and potential therapies in this disease. Mice with severe combined immunodeficiency (SCID) which will accept human xenografts have been useful in the study of a variety of human malignancies. CML has been difficult to establish in SCID mice possibly due to the lack of a functioning human stroma and relevant cytokines. To facilitate engraftment we injected cells in matrigel which is a soluble extract of basement membranes; is liquid below 22 degrees C and gels at 37 degrees C. CD34+ myeloid blast crisis cells (2 x 10(6)) were mixed in matrigel and injected subcutaneously into 10 SCID mice. All mice developed large tumours which spread to the mouse BM and spleen. However the percentage of human cells in the mouse BM and spleen was variable and ranged from 1 to 50 per cent. In contrast chronic phase (CP) CML cells mixed in matrigel did not form subcutaneous tumours and spread to the BM and spleen was detectable by PCR and not macroscopically. Groups of mice were injected with matrigel containing 1-20 x 10(7) MNC (2-20 x 10(5) CD34+ cells) from five patients with CP CMP. Bcr-abl sequences were detected by RT-PCR in the peripheral blood (PB) of 38/84 (45 per cent) mice at 3-10 weeks following injection of the CML cells but rarely at later time points. In addition, 33/75 (44 per cent) of mice sacrificed between 7 and 35 weeks following injection of CML cells were bcr/abl positive in the bone marrow and 17/70 (24 per cent) were positive in the spleen. Bcr-abl positive human CFU-GM colonies were also cultured from the murine bone marrow of several mice indicating that hematopoietic progenitor cells were able to migrate from the matrigel and engraft in murine hematopoietic organs. Engraftment of CP-CML was more successful in mice given higher numbers of CD34+ cells. Histological examination revealed that myeloid cells grow locally in the matrigel for several weeks, during which time the matrigel is infiltrated by blood vessels which may allow for the migration of CML progenitors to the murine bone marrow. This model system may be useful for studying the role of immunotherapy after allogeneic and autologous bone marrow transplantation.
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PMID:Engraftment of chronic myeloid leukemia in SCID mice. 1023 67

Unrelated donor (UD) bone marrow transplantation (BMT) represents an attractive option for patients with haematological, oncological or genetic diseases lacking a compatible familiar donor. Between September 1988 and December 1997 the search of a donor has been activated for 1724 patients in Italy. Until May 1998, 413 BMT from UD have been performed in 28 different authorized italian centres. Forty out of these patients were affected by genetic diseases apart from SCID (severe combined immunodeficiency). Sixty-month disease free survival (DFS) of this group was 62%. Seventy-four out of 215 children with acute lymphoblastic leukemia (ALL) for whom a donor search was started underwent a BMT. Six year DFS was 25%. Fifty-nine out of 379 patients with chronic myeloid leukemia (CML) for whom a donor search was activated underwent BMT. Forty-eight month DFS was 41.5%. Inborn errors curable with BMT, relapsed ALL and CML represent an absolute indication for UD BMT. In these cases donor search should be activated yearly.
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PMID:[Transplantation of bone marrow from unrelated donors in Italy: activity and results]. 1064 39

BCR-ABL is a chimeric oncogene generated by translocation of sequences from the chromosomal counterpart (c-ABL gene) on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, BCR-ABL(p190) and BCR-ABL(p210), are produced that are characteristic of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(1)-ALL). In CML, the transformation occurs at the level of pluripotent stem cells. However, Ph(1)-ALL is thought to affect progenitor cells with lymphoid differentiation. Here we demonstrate that the cell capable of initiating human Ph(1)-ALL in non-obese diabetic mice with severe combined immunodeficiency disease (NOD/SCID), termed SCID leukemia-initiating cell (SL-IC), possesses the differentiative and proliferative capacities and the potential for self-renewal expected of a leukemic stem cell. The SL-ICs from all Ph(1)-ALL analyzed, regardless of the heterogeneity in maturation characteristics of the leukemic blasts, were exclusively CD34(+ )CD38(-), which is similar to the cell-surface phenotype of normal SCID-repopulating cells. This indicates that normal primitive cells, rather than committed progenitor cells, are the target for leukemic transformation in Ph(1)-ALL.
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PMID:A primitive hematopoietic cell is the target for the leukemic transformation in human philadelphia-positive acute lymphoblastic leukemia. 1078 38


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