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Query: UMLS:C0596978 (Leukemia)
 15,069 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The majority of patients with chronic myelogenous leukemia (CML) have a characteristic reciprocal translocation between chromosome 9 and 22, resulting in the Philadelphia (Ph1) chromosome. During this translocation, the c-abl oncogene on chromosome 9 is transferred to the Ph1 chromosome and linked to a breakpoint cluster region (bcr), which is part of a large bcr gene. This phenomenon results in the formation of a bcr-c-abl fusion gene, which is transcribed into an 8.5 kb chimeric mRNA encoding a 210 kd bcr-c-abl fusion protein. The fusion protein has tyrosine kinase activity implicated in the pathogenesis of CML. The breakpoint near the c-abl locus on chromosome 9 can occur within a large area. In contrast, the breakpoints on chromosome 22 cluster within the bcr region of 5.8 kb. A chronic phase lasts for an average of 2 to 3 years; and, subsequently, most patients enter blast crisis. In the present study, we examined 15 Ph1-positive CML patients (eight in chronic phase, one in accelerated phase, and six in blast crises) as to whether the identifiable difference in the locations of the bcr breakpoints exist between CML patients in chronic phase and those in blast crisis. In seven of eight CML patients in chronic phase, in one in accelerated phase, and in four out of six CML patients in blast crisis, the bcr breakpoints clustered in the 3' portion of the bcr. Thus, we could not find out the correlation between the locations of the bcr breakpoints and the clinical stage of the CML patients. This might imply that blastic transformation in Ph1-positive CML was caused by other mechanisms than the transition of the bcr breakpoints.
Leukemia 1989 Jul
PMID:No correlation between locations of bcr breakpoints and clinical states in Ph1-positive CML patients. 273 54

The macrophage colony stimulating factor, CSF-1 (M-CSF) exerts its pleiotropic effects on hematopoietic cells of the mononuclear phagocyte series by binding to a single class of high affinity receptors encoded by the c-fms proto-oncogene. Binding of CSF-1 to its receptor activates an intrinsic tyrosine kinase activity, resulting in autophosphorylation of the receptor on tyrosine, rapid receptor down modulation, and phosphorylation of as yet unidentified physiologic substrates that initiate a mitogenic response. Transduction of a human CSF-1 receptor cDNA into mouse fibroblasts enables them to proliferate in response to human recombinant CSF-1, suggesting that the receptor gene contains all the information necessary to elicit a mitogenic response, even in cells which do not normally respond to the growth factor. The v-fms oncogene product has undergone genetic alterations which constitutively activate the receptor kinase in the absence of CSF 1. Insertion of the v-fms gene into macrophage or immature myeloid cell lines abrogates their dependence on hematopoietic growth factors and renders them tumorigenic in nude mice. Reconstitution of lethally irradiated mice with bone marrow stem cells containing the v-fms oncogene also induces clonal proliferation and, ultimately, frank malignancies of multiple hematopoietic lineages. Thus, constitutive activation of the CSF-1 receptor gene, either by mutation or gene rearrangement, might be expected to contribute to leukemia.
Leukemia 1988 Dec
PMID:The role of the CSF-1 receptor gene (C-fms) in cell transformation. 284 91

Kinases which phosphorylate proteins on tyrosine residues are of importance in the control of both normal and malignant cell proliferation. The receptors for a number of growth factors have intracellular domains with tyrosine protein kinase activity and several viral oncogenes code for tyrosine protein kinases. An abnormal tyrosine protein kinase has been implicated in the pathogenesis of chronic granulocytic leukemia. Using an immunoblot method and an antiphosphotyrosine antibody, we have detected substrates of tyrosine protein kinases in fresh human leukemia cells and normal blood and bone marrow cells. These substrates were present in all types of cells examined. Cells from patients with acute lymphoblastic leukemia, acute myeloid leukemia, and chronic lymphocytic leukemia contain prominent phosphotyrosine-containing protein bands with molecular weights in excess of 95 kDa. By contrast, chronic granulocytic leukemia cells, as well as normal bone marrow cells, lymphocytes, and monocytes, contain predominantly low molecular weight (less than 95 kDa) tyrosine kinase substrates. When lymphocytes were stimulated to enter cell cycle, however, high molecular weight substrates of similar molecular weights to those detected in acute lymphoblastic leukemia, acute myeloid leukemia, and chronic lymphocytic leukemia became prominent. The implications of these findings in the control of normal and malignant cell proliferation and differentiation are discussed.
Leukemia 1987 Nov
PMID:Detection of tyrosine protein kinase substrates in fresh leukemia cells and normal blood cells using an immunoblotting technique. 331 58

We investigated the effect of ubenimex on the growth and differentiation of U937 cells, a histiocytic lymphoma cell line. Ubenimex is a dipeptide ((2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl-L-leucine) and an inhibitor of aminopeptidase B produced by Streptomyces olivoreticuli. Ubenimex inhibited the proliferation of U937 cells in a dose-dependent manner. Ubenimex-treated U937 cells showed condensation of nuclear chromatin, increase of cytoplasmic vacuoles and more intense nonspecific esterase staining compared with untreated U937 cells. Expression of CD13 and CD68 detected by monoclonal antibodies My7 and EBM11, respectively, was enhanced by ubenimex, but the expression of CD4 detected by MT310 was significantly decreased. The effects of ubenimex on U937 cell growth inhibition and enhancement of monocytic cell surface marker expression on U937 cells were reversible when cultivated without ubenimex for more than 6 days. In addition, the bactericidal activity of U937 cells was increased by ubenimex treatment, and was further enhanced by treatment with macrophage colony-stimulating factor (M-CSF). Furthermore, ubenimex augmented the expression of M-CSF receptors by U937 cells and enhanced the tyrosine kinase activity of cellular pp60c-src. These findings indicated that ubenimex inhibited the proliferation of U937 cells and induced morphological, cytochemical and functional differentiation into monocyte/macrophages.
Leukemia 1994 Dec
PMID:Effect of ubenimex on the proliferation and differentiation of U937 human histiocytic lymphoma cells. 752 60

The src-related tyrosine kinase p56lck is overexpressed in the mouse leukemia cell line LSTRA. Although p56lck is thought to be a specific T-cell marker, we found that LSTRA cells can be induced to differentiate towards macrophages or granulocytes by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate or the cyclic nucleotide analogue, dibutyryl cAMP, respectively. Treatment of LSTRA cells with 12-O-tetradecanoylphorbol-13-acetate resulted in marked alterations in morphology including increased size, adherence, and spreading on culture dishes. These cells also ceased proliferating, accumulated in G0-G1 and expressed nonspecific esterase activity. In contrast, although LSTRA cells treated with dibutyryl cAMP stopped growing and accumulated in G0-G1, these cells expressed functionally active chemotactic peptide receptors and became irregular and granular in appearance. Differentiation of LSTRA cells was also found to be associated with altered expression of p56lck. Thus, while 12-O-tetradecanoylphorbol-13-acetate treatment caused the cells to produce higher molecular weight forms of p56lck, dibutyryl cAMP treatment resulted in increased expression of total p56lck mRNA as well as the more mature type II p56lck mRNA transcript. There were no major alterations in p56lck kinase activity in vitro following differentiation. Phospholipase C gamma and p21rasGAP, two putative substrates for the tyrosine kinase activity of p56lck, were found to be constitutively phosphorylated on tyrosine in LSTRA cells. Tyrosine phosphorylation of these substrates was not altered following differentiation. These results indicate that LSTRA cells are relatively early precursors that have the capacity to develop along the myeloid differentiation pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alterations in expression of p56lck during myeloid differentiation of LSTRA cells. 753 90

A patient with a chronic myeloproliferative disease associated with a 100% t(5;12) translocation was treated with 3 million U per day of IFN-alpha 2a. Besides being consistently Ph-negative, the search for BCR/ABL hybrid transcripts by means of RT-PCR was also negative. Total cytogenetic conversion to diploid hematopoiesis was obtained, but after discontinuation of IFN a 50% relapse of t(5;21) mitoses was found, and treatment was resumed. There is some degree of consensus that the mechanism by which IFN-alpha suppresses the Ph+ clone in CML consists in the restoration of normal adhesion of CML progenitors to the marrow stroma, by preventing transcription of the BCR/ABL mRNA, and hence expression of the p210 tyrosine kinase. However, if the 'faulty adhesion' hypothesis, and its correction by IFN-alpha, is to be considered correct, this case proves that it must include also Ph-negative, not BCR-ABL rearranged clonal myeloid proliferations.
Leukemia 1995 Jun
PMID:Chronic clonal myeloproliferative disease associated with a t(5;21) translocation. Complete but transient hematologic and cytogenetic remission induced by interferon-alpha. 759 88

The GM-CSF receptor belongs to the cytokine receptor superfamily. The high-affinity receptors of this class are lacking intrinsic tyrosine kinase domains. The GM-CSF receptor consists of alpha and beta subunits. The beta subunit is shared with the receptors of IL-3 and IL-5. In addition to the membrane bound forms the receptors have been found to possess soluble isoforms. Since retroviral infection of the human GM-CSF dependent cell line, TF-1, leads to factor independent growth by increased expression of the GM-CSF receptor alpha chain in a subgroup of infected clones, we were interested in studying the role of this chain in human AML. Further considering that a point mutation in the extracellular domain of the erythropoietin receptor, also a member of the cytokine receptor superfamily, resulted in constitutive activation of a murine cell line, we investigated the possibility that a point mutation of the GM-CSF receptor was responsible for autonomous growth of AML cells. We sequenced a segment of the receptor coding for the extracellular domain of the alpha subunit. cDNA was prepared from peripheral blood or bone marrow cells from 24 patients with AML, from four patients with MDS and from three human myeloid cell lines. The region of interest was amplified with two rounds of PCR reactions with nested primers, covering five overlapping fragments, and directly sequenced using a non-radioactive technique. No point mutations were found in the investigated samples. Thus, point mutations in this segment of the GM-CSF receptor gene do not seem to play an important role in the transformation process of human acute leukemia.
Leukemia 1995 Jan
PMID:Absence of point mutations in the extracellular domain of the alpha subunit of the GM-CSF receptor in a series of patients with acute myeloid leukemia (AML). 784 15

Interleukin-6 is a multifunctional cytokine which regulates various aspects of the host immune response. Here we show that signaling events transferred by IL-6 in monocytes and the U937 human monocytic leukemia cell line lead to the phosphorylation of the small heat shock protein (Hsp)27. Phosphorylation of Hsp27 is both dose- and time-dependent. In the absence of NaF, a serine/threonine phosphatase inhibitor, IL-6 failed to initiate Hsp27 phosphorylation in vitro. IL-6 also failed to phosphorylate Hsp27 when cells had been deactivated with tyrosine kinase inhibitors such as genistein. The capacity of cellular extracts to phosphorylate Hsp27 could be, however, restored when either immunoprecipitated activated MAP kinase or purified MAPKAP kinase 2 was added to cell lysates. These findings suggest that IL-6-mediated phosphorylation of Hsp27 results from activation of MAPKAP kinase 2, a serine/threonine kinase which is activated by MAP kinase. Taking together, our findings indicate that IL-6-induced activation of MAP kinase by IL-6 entails the activation of MAPKAP kinase 2 and subsequent phosphorylation of the Hsp27.
Leukemia 1995 Feb
PMID:Interleukin (IL)-6 signaling leads to phosphorylation of the small heat shock protein (Hsp)27 through activation of the MAP kinase and MAPKAP kinase 2 pathway in monocytes and monocytic leukemia cells. 786 66

Chronic myelogenous leukemia (CML) is characterized by the presence of a specific chromosomal translocation between the long arms of chromosomes 9 and 22 that results in the fusion of BCR encoded sequences upstream of exon 2 of c-ABL. This fusion gene produces a 210-kDa chimeric BCR-ABL protein that has elevated tyrosine kinase activity. Several substrates of this activated tyrosine kinase have been reported. However, their necessity for the transforming functions of BCR-ABL has not been determined. A specific deletion of the SH2 domain of ABL was created to determine whether this mutation would alter the ability of BCR-ABL to induce factor-independent growth of a murine myeloid cell line and to determine whether the SH2 domain mediates the interaction of BCR-ABL with any of its substates. Our results indicate that the SH2 domain of BCR-ABL is not required for the induction of growth factor independence and is not required for the association of BCR-ABL with rasGAP or SHC. However, myeloid cells expressing this mutant lack the tyrosine phosphorylation of a 62-kDa rasGAP associated protein.
Leukemia 1995 Feb
PMID:The SH2 domain of ABL is not required for factor-independent growth induced by BCR-ABL in a murine myeloid cell line. 786 67

The gene which causes X-linked agammaglobulinemia, btk, has recently been identified as a cytoplasmic tyrosine kinase expressed almost exclusively in B cells, and at all stages of B-cell differentiation. To assess the possibility of involvement of this gene in childhood B-cell malignancies, cells from 23 pediatric patients with B-cell acute lymphoblastic leukemia were examined for expression and alteration of the Btk protein and also for mutations in the btk gene. Btk proteins, similar in both molecular weight and quantity to those seen in unaffected individuals, were detected in whole cell lysates from the blasts of 12/12 patients indicating that no abnormal protein was present. cDNAs from the leukemic blasts of all 23 patients were screened with specific primers covering the coding region of the btk cDNA for mutations using single strand conformation polymorphism (SSCP) analysis. No mutations were found but a nucleotide polymorphism was identified in 4/23 patients at the 3' end of btk. Although the sample size in this study was relatively small, these data suggest that btk does not appear to play a critical role in childhood B-cell leukemias.
Leukemia 1994 Apr
PMID:Expression of the X-linked agammaglobulinemia gene, btk in B-cell acute lymphoblastic leukemia. 815 53


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