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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abelson murine leukemia virus (A-MuLV) carries the gene v-abl, one of a group of oncogenes with structural and functional (tyrosine kinase) homology to three growth factor receptors. Work in this and other laboratories has shown that A-MuLV infection can render myeloid and lymphoid cells independent of the growth factors interleukin 3 and granulocyte-macrophage colony-stimulating factor. We have now shown that v-abl can also relieve interleukin 2 (IL-2) dependence in T cells. We infected a cloned IL-2-dependent antigen-specific cell line. Transformed cells were generated which were factor independent and tumorigenic. The transformants each bore unique v-abl DNA inserts and expressed v-abl mRNA. No elevation of expression of either IL-2 or its receptor could be detected in these cells. Thus, A-MuLV can short-circuit the dependence of hematopoietic cells on IL-2, IL-3, and possibly granulocyte-macrophage colony-stimulating factor, none of whose receptors are known to be of the tyrosine kinase type.
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PMID:Abelson virus transformation of an interleukin 2-dependent antigen-specific T-cell line. 303 52

Tyrosine-specific protein kinases that transfer the terminal phosphate from ATP to protein acceptors are associated with certain transforming viruses and cell surface growth factor receptors. Here we describe the synthesis and testing of potential multisubstrate inhibitors of this class of enzymes. The inhibitors were prepared by covalent attachment of the terminal phosphate of ATP or its tetraphosphate analogue to tyrosine mimics. Testing against p60v-abl, the tyrosine kinase from the Abelson murine leukemia virus, showed that the series of inhibitors was moderately potent (IC50 values as low as 13 microM). However, structural modification of the tyrosine mimic, including replacement with a serine-like moiety, had little effect on potency. It is therefore concluded that the ATP moiety is largely responsible for binding and that the enzyme requires additional structural features for recognition of the tyrosine-containing substrate.
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PMID:Synthesis and evaluation of multisubstrate inhibitors of an oncogene-encoded tyrosine-specific protein kinase. 2. 304 21

Activation of the oncogenic potential of c-abl proto-oncogene has been correlated with the activation of its tyrosine kinase activity. The oncogenes derived from c-abl, e.g., gag/v-abl in Abelson murine leukemia virus or bcr/abl in chronic myelogenous leukemia, lack N-terminal coding sequences of the normal c-abl gene. In mouse and human cells, two sets of N-terminal amino acids encoded by 5'-variable exons are found in c-abl proteins. To assess the importance of N-terminal deletion in the activation of c-abl tyrosine kinase, a full length or an N-terminal deleted c-abl protein was expressed in bacteria and in monkey COS cells. Measurements of the autokinase activity of these two c-abl proteins showed that deletion of the N-terminal amino acids led to a three to five fold increase of the c-abl tyrosine kinase activity. Thus, the N-terminal deletion is important in the activation of c-abl proto-oncogene.
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PMID:Negative regulation of c-abl tyrosine kinase by its variable N-terminal amino acids. 314 98

To evaluate the role of the human T-cell-specific tyrosine kinase lck (YT16), we measured the levels of lck expression in thymocytes, peripheral T-cells, and leukemia T-cell lines which are arrested at different stages of thymic differentiation. The results indicate that higher levels of the lck message can be found in total thymocytes and T-cells arrested at Stage III (thymocytes that have rearranged their alpha, beta, and gamma chain T-cell receptor genes). A 20-fold lower level of these transcripts, however, can be found in cells derived from Stage I cells (thymocytes with germline alpha, beta, and gamma genes), 4 times less messages in Stage II cells (thymocytes with rearranged gamma and beta chain genes, but with germline alpha chain genes), and a 4-fold lower amount of RNA in Stage IV cells (mature lymphocytes). Culture of these cells with a variety of inducing reagents indicated that leukemia cell lines of only Stages I and II can be induced to increase their levels of YT16 expression by the addition of tetradecanoyl phorbol-13-acetate. These results suggest that there may be a developmental regulation of these tyrosine kinase messages during T-cell ontogeny. The high level of these transcripts in more mature T-cell leukemia lines suggests that they may primarily play a role in the proliferative controls of these cells.
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PMID:Expression of the human T-cell-specific tyrosine kinase YT16 (lck) message in leukemic T-cell lines. 325 10

We report a case of acute leukemia in which studies at presentation showed both myeloid and lymphoid cell surface markers. At relapse membrane markers studies were consistent with a leukemia of B-lymphoid lineage. However, immunoglobulin (Ig) and T cell receptor (TCR) beta chain genes were both found in a rearranged configuration. The majority of metaphases from the leukemic cells at presentation showed the Philadelphia chromosome, t(9;22)(q34;q11), whereas a minority were normal. At relapse both Ph-positive and -negative metaphases were still present in the bone marrow but some of the Ph-negative metaphases had acquired an additional chromosome #19 [47,XY, + 19]. Southern analysis of DNA from leukemic bone marrow cells at diagnosis showed no rearrangement of breakpoint cluster region (bcr). There was no bcr-abl chimeric mRNA typical of Ph-positive chronic myeloid leukemia (CML). However, the cells expressed an abl-related protein of Mr 190 kd with enhanced tyrosine kinase activity. Leukemic cell metaphases were studied by the technique of in situ hybridization with probes for C-lambda, sis, abl, and 5' bcr. The c-abl probe mapped to chromosome 22q11 in Ph-positive metaphases. The 5' bcr probe mapped to 9q+ in the Ph-positive metaphases and the C-lambda gene mapped to the Ph chromosome. Thus, the genomic breakpoint in this patient must lie upstream of the BCR defined by study of Ph-positive CML and downstream of the C-lambda gene locus. We speculate that the Ph-negative cells in this patient may represent a leukemic proliferation susceptible to acquisition of specific chromosomal changes.
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PMID:The genomic breakpoint in a patient with Philadelphia-positive acute leukemia is 5' of the breakpoint cluster region. 325 55

Abelson murine leukemia virus (A-MuLV) has been shown to abrogate the requirement for growth factor interleukin-3 (IL-3) in a variety of hematopoietic cell lineages by a non-autocrine mechanism. By infecting an IL-3 dependent myeloid cell line, FDC-P1, with A-MuLV containing temperature sensitive tyrosine kinase mutants of the v-abl oncogene, cell lines with temperature sensitive IL-3 independence phenotype were established. At the permissive temperature, cells expressing the ts oncogenes contained 20 fold higher levels of tyrosine-phosphorylated proteins than uninfected cells and were completely IL-3 independent. When shifted to the restrictive temperature, ts A-MuLV infected cells still contained 5 to 10 fold higher levels of phosphotyrosine but became dependent on IL-3 for growth. These results demonstrate that the maintenance of A-MuLV induced IL-3 independence requires the continuous function of the v-abl oncogene.
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PMID:Reversible dependence on growth factor interleukin-3 in myeloid cells expressing temperature sensitive v-abl oncogene. 325 2

The ABL proto-oncogene on the Philadelphia chromosome is 'activated' by its translocation in a manner similar to its activation by the murine Abelson leukemia virus--with the formation of a fusion protein with a new N-terminus and enhanced tyrosine kinase activity. Study of this BCR-ABL fusion gene has led to the development of molecular probes which are beginning to play an important role in the diagnosis and clinical management of chronic myelogenous leukemia, and may ultimately lead to better understanding of the biology of the disease. The role of ABL on the Philadelphia chromosome in acute lymphoblastic leukemia is only now beginning to be understood, but is likely to be similar, and a new ABL species has already been identified by several groups. It is likely that this protein is the product of a fusion gene, as it is in chronic myelogenous leukemia, but definitive proof awaits molecular cloning of the translocation breakpoint. Aside from its activation by the Ph1 chromosome, ABL has not been found to have a role in any other human cancer.
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PMID:The ABL oncogene in human leukemias. 328 49

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 report the isolation and nucleotide sequence of a 3.7-kilobase (kb) cDNA clone from chicken spleen corresponding to a previously undescribed member of the src family of protooncogenes. It encodes a protein with a C-terminal domain related to the src family of protein-tyrosine kinases (EC 2.7.1.112) and, among these, has most significant homology to the lck gene isolated from a murine leukemia virus-induced thymoma cell line. The gene is therefore referred to as c-tkl for cellular tyrosine kinase related to lck. Analysis of genomic DNA reveals that c-tkl is a chromosomal locus distinct from c-src and c-lck. Furthermore, the size of c-tkl mRNA as well as its pattern of expression indicates that it is not the chicken homologue of lck but a different gene. A 3.8-kb transcript of the c-tkl gene, identical to the size determined for c-src mRNA, was observed in cultured chicken embryo fibroblasts and in chicken spleen and brain. In contrast, detection of a definite c-src mRNA signal with mRNA from spleen was not possible under the hybridization conditions employed when the 5' end of v-src was used as the probe, and none of the 11 clones obtained from the cDNA library corresponded to a c-src transcript. Thus previous studies of c-src mRNA expression in spleen may have actually detected c-tkl transcripts.
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PMID:Additional member of the protein-tyrosine kinase family: the src- and lck-related protooncogene c-tkl. 332 Oct 53

A great deal of information has emerged over the past decade regarding the gene structures and corresponding protein products of the cellular and transformation-associated forms of the ABL tyrosine kinase family. Many reports have also detailed the biological effects of these proteins (particularly the viral ABL forms) on a broad range of cell types. However, in spite of all these research efforts, the precise role of the ABL gene in normal and neoplastic growth remains to be determined. To elucidate the mechanism of action of normal and altered ABL proteins, it is imperative to identify their relevant cellular substrates and establish the role of the ABL target proteins in transformation and normal cellular growth. The availability of temperature-sensitive ABL proteins, coupled with the use of sensitive anti-phosphotyrosine antibodies, should be useful in this respect. Purification of enzymatically active, intact forms of the ABL proteins produced in insect cells by employing baculovirus expression vectors should permit direct comparison of the biochemical properties and tertiary structures of the various members of the ABL protein kinase family. Such studies will aid in understanding the nature of the alteration of ABL which results in the activation of its transforming potential. Furthermore, the availability of purified ABL proteins should permit examination of interactions of ABL with other growth-regulatory proteins, such as growth factor receptors. It has been shown that transformation-associated ABL proteins interact with the IL-3, IL-2 and GM-CSF growth-factor pathways. These and other components of the cellular signalling pathways are potential ABL targets. The elucidation of ABL function by a variety of approaches such as those described above will ultimately aid in the development of far-reaching therapeutic treatments for at least two forms of human leukaemia: Ph positive CML and Ph positive ALL.
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PMID:Role of the ABL oncogene tyrosine kinase activity in human leukaemia. 333 51


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