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

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.
 ...
PMID:Expression of human adenosine deaminase from various strong promoters after gene transfer into human hematopoietic cell lines. 275 48

A 60-year-old patient with Ph1 + ve CGL presented with blast crisis. The leukaemic blast cells resembled erythroblasts and had 51 chromosomes with two Ph1. Cells obtained from peripheral blood, marrow and a pleural effusion were cultured under a variety of conditions. After 2-3 weeks in culture, the model 51-chromosome line persisted but many of the cells displayed erythroid morphology and differentiated to resemble mature normoblasts, strongly positive on o-tolidine +ve staining. Haemoglobin analysis by starch gel and globin synthesis studies demonstrated only fetal haemoglobin (HbF) synthesis in the cultured cells whilst the patient's reticulocytes synthesized very little HbF. Restriction enzyme mapping of DNA from the cultured cells showed that beta-globin genes were still present in these cells even though they were not expressed.
 ...
PMID:Erythroid differentiation in CGL cells from a patient with blast crisis. 659 Sep 36

Various chemicals which are known to have positive effects on differentiation of some erythroid cell lines were tested on a human chronic myelogenous leukemia cell line, KU-812F. Succinic acid, 5-azacytidine, daunomycin, and hemin showed a positive effect. Among them, hemin and 5-azacytidine were the most effective inducers for erythroid differentiation of KU-812F cells. Dimethylsulfoxide, cytosine arabinofuranoside, and sodium n-butyrate showed no effect. In addition, subclone KU-812F/33 derived from the KU-812F cell line showed differential expression of the beta- and gamma-globin genes in the presence of either 2 microM 5-azacytidine or 40 microM hemin. Hemoglobin synthesis in differentiated KU-812F/33 cells was analyzed by isoelectric focusing gel electrophoresis, and S1 mapping analysis of beta- and gamma-globin mRNA was performed. After treatment with 5-azacytidine, the beta-globin gene expression was predominantly enhanced (18.75-fold higher level of beta-globin mRNA). After treatment with hemin, the most notable increase was in the gamma-globin gene expression (1.83-fold higher level of gamma-globin mRNA), while no increment of beta-globin was observed.
 ...
PMID:Differential induction of adult and fetal globin gene expression in the human CML cell subline KU-812F/33. 752 36

Juvenile chronic myelocytic leukemia (JCML) is a rare disorder of early childhood. Characteristic of JCML are the progressive appearance of high levels of fetal hemoglobin (HbF), reflecting a true reversion to a fetal type of erythropoiesis, and the presence of colony-forming cells able to grow in vitro spontaneously in the absence of growth factors. To better understand the relationship between the erythroid abnormalities and the leukemic process, we analyzed the expression pattern of specific genes related to erythroid differentiation--GATA-1, EPOR, alpha-globin, beta-globin, and gamma-globin genes--in JCML peripheral blood (PB) cells and in vitro-derived colonies. Northern blot analysis of PB cells from five JCML patients indicated levels of GATA-1 transcripts much higher than those usually found in other types of leukemic cells, and S1 nuclease protection assay detected significantly increased expression of gamma-globin mRNA. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of single granulocyte-macrophage colony-forming unit (CFU-GM) colonies, obtained in vitro in the absence of added growth factors from four JCML patients, detected GATA-1, EPOR, and globin (alpha and gamma) transcripts in most of the colonies tested, in contrast with control CFU-GM from normal bone marrow, which were positive only for GATA-1. Single JCML colonies were tested for the presence of two different transcripts; whereas alpha- and gamma-globin genes appeared mostly coexpressed, beta-globin mRNA was detected only in a minority of the gamma-globin-positive colonies, indicating that the leukemic pattern of hemoglobin synthesis is mainly fetal. In addition, the leukemic cells occurring during blast crisis of one of our patients displayed the typical features of a stem cell leukemia (CD34+, CD19-, CD2-, myeloperoxidase-). In this sorted CD34+ population, we detected the presence of a marker chromosome, der(12)t(3;12), previously identified in bone marrow cells at diagnosis and an expression pattern superimposable to that of the JCML colonies, consistently displaying a high gamma-globin:beta-globin mRNA ratio. The expression of erythroid markers within populations of leukemic cells, both in vivo and in vitro, supports the hypothesis that abnormal JCML erythroid cells may originate from the same mutated progenitor that sustains the growth of the leukemic cells.
 ...
PMID:Constitutive expression of GATA-1, EPOR, alpha-globin, and gamma-globin genes in myeloid clonogenic cells from juvenile chronic myelocytic leukemia. 779 40

Induction of specific gene expression may provide an alternative or a support to conventional cytotoxic chemotherapy of cancer, as well as to therapy for sickle cell diseases. In this respect, pharmacological induction of expression of the endogenous gamma-globin gene is a realistic approach to therapy of beta-globin disorders. Erythroid differentiation and inhibition of proliferation of the human CML K562 cell line was induced by guanosine 5'-triphosphate (GTP). The hemoglobin production in cells was correlated to an increase in alpha- and gamma-globin mRNA expression. At the transcriptional level, we showed that both the expression of the major erythroid transcription factor GATA-1 (protein and mRNA) and its binding capacity to the gamma-globin gene promoter was transiently increased. Moreover, GTP moderately stimulated the gamma-globin gene promoter after 48 h of treatment. At the post-transcriptional level, GTP treatment led to a drastic increase of the gamma-globin mRNA half-life. This stabilizing effect of GTP was mediated via the 3'-untranslated region (3'-UTR) of the gamma-globin mRNA. In conclusion, mechanism of GTP-mediated differentiation of K562 cells is linked to an early activation of gamma-globin gene transcription followed by a stabilization of its mRNA.
 ...
PMID:GTP-mediated differentiation of the human K562 cell line: transient overexpression of GATA-1 and stabilization of the gamma-globin mRNA. 1099 5

BCR-ABL oncogene, the molecular hallmark of chronic myelogenous leukemia (CML) arises in a primitive hematopoietic stem cell with both differentiation and self-renewal ability. To study the phenotypic effects of BCR-ABL in a clonal in vitro self-renewal and differentiation model, we have introduced BCR-ABL in the ES cell line CCE. The major effect of BCR-ABL expression was the persistence of primitive morphology of ES cells despite LIF deprivation, correlated with a constitutive activation of STAT3, the major self-renewal factor of ES cells, but no evidence of activation of STAT5. The enforced expression of BCR-ABL in an ES cell line, engineered to express a tetracycline-inducible dominant-negative form of a STAT3, triggered ES cell differentiation with an increased generation of hematopoietic cells expressing erythroid and megakaryocytic phenotypes. RT-PCR analysis for Oct4, Brachyury and beta-globin expression confirmed a delay of differentiation in BCR-ABL expressing clones, which could be entirely reversed upon activation of the dominant-negative form of STAT3. To study the possible relevance of STAT3 activation by BCR-ABL in human CML, Western blot analyses performed on the CD34+ cells, purified from CML patients at different stages of their disease, also demonstrated increased levels of STAT3 proteins phosphorylated both on tyrosine and serine residues. These results represent to our knowledge the first functional link between BCR-ABL oncogene and a self-renewal in the context of ES cells through constitutive activation of STAT3. Thus, the BCR-ABL embryonic stem cell model that we developed as well as the results obtained in human CML samples suggests a role for STAT3 in the pathogenesis of human CML.
 ...
PMID:Constitutive and specific activation of STAT3 by BCR-ABL in embryonic stem cells. 1282 44

The growth factor-independent erythroleukemic cell line ERY-1 was established from the peripheral blood of a 87-year-old woman with chronic myeloid leukemia (CML) in the acute phase. Immunophenotyping showed that fresh leukemic cells were positive for CD13, CD33, CD36 and CD235a (glycophorin A), a phenotype compatible with that of erythroblastic cells. Cytogenetic and fluorescence in situ hybridization (FISH) analysis demonstrated classical t(9;22)(q34;q11) chromosomic translocation associated with a duplication of the BCR-ABL fusion gene. Other cytogenetic abnormalities were detected in all analyzed mitosis, the most frequent being a trisomy of chromosome 8. The established ERY-1 cell line retains these immunophenotypic and cytogenetic features, and light and electron microscopy confirmed the relatively mature erythroblastic phenotype of the cells. In addition, ERY-1 cell line expressed beta-globin mRNA and a non-phosphorylable form of the erythropoietin receptor, even in presence of erythropoietin. Of note, the proliferation of ERY-1 cells was inhibited by TGFbeta1 or STI-571 (Gleevec), without significant induction of further differentiation. In conclusion, ERY-1 is a new growth factor-independent human erythroleukemic cell line with a relatively mature phenotype that may be useful to study the molecular events involved in erythroblastic differentiation.
 ...
PMID:Establishment and characterization of a new human erythroleukemic cell line, ERY-1. 1547 75

Human chronic myelogenous leukemia (CML) cell line K562 can be chemically induced to differentiate and express embryonic and fetal globin genes. In this study, the effects of doxorubicin (DOX), an inducer of K562 cell erythroid differentiation, with those of epidoxorubicin (EDOX) as well as newly synthesized derivatives of both drugs (DOXM, DOXH, and EDOXM) on cell growth and differentiation were compared. Our results revealed that DOX, EDOX and their derivatives caused irreversible differentiation of K562 cells into more mature hemoglobin-containing cells. This phenomenon was linked to time-dependent inhibition of cell proliferation. Considering the impact of the structure of newly synthesized anthracyclines on their cellular activity, our data clearly indicated that among tested anthracyclines DOXM, a morpholine derivative of DOX exerted the highest antiproliferative and differentiating activity. An increase of gamma-globin mRNA level caused both by high transcription rate and by mRNA stabilization, as well as an enhancement of expression but not activity of erythroid transcription factor GATA-1 were observed. Therefore, a high level of hemoglobin-containing cells in the presence of DOXM resulted from transcriptional and post-transcriptional events on gamma-globin gene regulation. The same morpholine modification introduced to EDOX did not cause, however, similar effects on cellular level. Characterization of new powerful inducers of erythroid differentiation may contribute to the development of novel compounds for pharmacological approach by differentiation therapy to leukemia or to beta-globin disorder, beta-thalassemia.
 ...
PMID:Accumulation of gamma-globin mRNA and induction of irreversible erythroid differentiation after treatment of CML cell line K562 with new doxorubicin derivatives. 1709 70