Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human granulocyte colony-stimulating factor (G-CSF) rapidly loses the biological activity and the receptor binding capacity following radioiodination. We have made a mutein of human G-CSF, KW-2228, in which Thr-1, Leu-3, Gly-4, Pro-5, and Cys-17 were respectively substituted with Ala, Thr, Tyr, Arg, and Ser; showed more potent G-CSF activity; and retained full biological activity and receptor binding capacity at least 2 weeks of radioiodination. G-CSF is an effective growth factor for the blasts of myeloid leukemia. Radioiodinated KW-2228 was prepared using solid-phase glucose oxidase-lactoperoxidase. Human leukemia cell lines and the blast cells from leukemia patients were examined for binding. High affinity binding sites were identified on myeloid cell lines and on the blasts obtained from acute myeloid leukemia patients. Scatchard analysis showed that a single binding site for G-CSF was observed (361-1688 receptors/cell; Kd 128-1400 pM). In contrast, specific binding of 125I-KW-2228 was not demonstrated on lymphoblastic cell lines or the blast cells of acute lymphoid leukemia or lymphoma. This difference was reflected in the effectiveness of G-CSF to stimulate colony formation in acute myeloid leukemia blasts, while G-CSF did not stimulate colony formation of the blast cells from acute lymphoid leukemia.
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PMID:Receptor binding of human granulocyte colony-stimulating factor to the blast cells of myeloid leukemia. 168 9

DNA from 161 patients with various forms of hematologic malignancies were investigated for mutations in exons 1 and 2 of the N-RAS, K-RAS and Ha-RAS gene by direct sequencing of DNA amplified in vitro by the polymerase chain reaction. Mutations involving either codons 11, 12, or 13 of the N-RAS gene were identified in 18 of the 161 patients. The relative frequencies of N-RAS gene mutations in these hematologic disorders was as follows: acute myelogenous leukemia (AML), 15%; acute lymphoblastic leukemia (ALL), 14%; myelodysplastic syndromes, 24%; and myeloid and lymphoid blast crisis of chronic myelogenous leukemia (CML), 3%. No correlation was observed between the presence of mutations and cytologic features or immunophenotype of these malignancies. Mutations involving codons 12 or 13 were equally prevalent, with a glycine to aspartic acid substitution being the most frequently encountered change. A single T-ALL case had a codon 11 mutation resulting in substitution of alanine with threonine. We failed to find mutations in exons 1 and 2 of the K-RAS or Ha-RAS genes in any case except a single AML with a mutation in codon 61 of the K-RAS gene. Also, no mutations were identified in chronic phase of CML, chronic lymphocytic leukemia. Ph1 positive ALL, non-Hodgkin's lymphoma, Hodgkin's disease, or multiple myeloma. These results indicate that RAS mutations, especially those involving exon 1 of the N-RAS gene, are frequent only in a subset of hematologic malignancies.
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PMID:The pattern of mutational involvement of RAS genes in human hematologic malignancies determined by DNA amplification and direct sequencing. 218 88

The 8;21 translocation, t(8;21)(q22;q22.3), is seen only in acute myelogenous leukemia and is characteristically associated with the M2 subtype. Subsequent to our identification of the t(8;21) breakpoint region on chromosome 21, we reported that the translocation results in the fusion of the AML1 gene on chromosome 21 with a novel gene on chromosome 8 which we called ETO (for eight twenty-one). Recently, the AML1 portion of the fusion protein has been shown to correspond to the DNA-binding and dimerization domains of the mouse gene, polyoma enhancer binding protein 2 alpha B (pebp 2 alpha B). We report here the complete sequence of the ETO portion of the fusion transcript as compiled from complementary DNAs from a t(8;21) AML patient and compare this with the ETO sequence from a mouse brain transcript. The deduced amino acid sequences are 99% identical. ETO has several features consistent with it being a transcription factor. The ETO sequence is different from the portion of PEBP 2 alpha B it replaces in the AML1/ETO fusion protein, except for their common high content of proline, serine, and threonine residues. Because neither the putative zinc fingers nor the TAF110 homology domain of ETO is present in PEBP2 alpha B, one might expect functional differences in the ability of AML1/ETO protein to affect the levels of transcription of genes normally regulated to some degree by AML1 (PEBP2 alpha B) during myeloid differentiation. The relatively high levels of ETO in developing brain suggest that it could be involved in the regulation of some aspect of neural proliferation or differentiation.
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PMID:The ETO portion of acute myeloid leukemia t(8;21) fusion transcript encodes a highly evolutionarily conserved, putative transcription factor. 813 93

The intracytoplasmic tail of the granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) beta c chain is essential for the activation of ligand-mediated signal transduction pathways in myeloid cells. Alterations in this region could deregulate normal signalling processes. We have therefore used RT-PCR-SSCP analysis of the receptor tail to look for point mutations in RNA from 35 patients with acute myeloid leukaemia (AML) and 10 haematologically normal controls. Patterns differing from those of the haemopoietic cell line TF-1 were detected in 25/35 (71%) AML patients and 8/10 (80%) normal controls. A total of six base substitutions were identified by sequencing. Three were conservative for the amino acid involved, three led to amino acid differences, valine652-->methionine, glycine647-->valine and proline603-->threonine. One alteration was found only in a normal control, the other five were all found in both AML patients and normal controls suggesting that they were DNA polymorphisms. Two substitutions were particularly common with allele frequencies of 0.23 (G1972-->A, unchanged proline648) and 0.13 (C1306-->T, unchanged serine426). These results indicate that the GM-CSFR beta c chain is highly polymorphic but point mutations of the intracytoplasmic tail do not appear to contribute frequently to the pathogenesis of AML.
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PMID:The beta subunit common to the GM-CSF, IL-3 and IL-5 receptors is highly polymorphic but pathogenic point mutations in patients with acute myeloid leukaemia (AML) are rare. 855 16

Deletion mutants of the intracytoplasmic domain of the granulocyte colony stimulating factor receptor (G-CSFR) have shown that it contains a membrane-proximal region which must be conserved to allow the receptor to transduce a mitotic signal, and a C-terminal region necessary for transduction of cell differentiation. Changes in the intracytoplasmic domain may result in the uncoupling of these two processes, as in acute leukaemia, and such alterations could occur either as isoforms or mutations. We have studied the transmembrane domain and intracytoplasmic tail of the G-CSFR in RNA from blood or bone marrow of 11 haematologically normal controls and 40 patients with acute myeloid leukaemia (AML). Two novel transcripts of the receptor were identified, both were minor components and are unlikely to be of major physiological significance. We could find no evidence for altered levels of expression of these transcripts in the AML patients. In addition, only one point mutation was detected in the 40 patients screened by RT-PCR-SSCP, a C-->A substitution at nucleotide 2088 which changes a threonine to asparagine in the transmembrane domain and is probably a polymorphism. These results suggest that abnormalities in the G-CSFR are uncommon in AML.
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PMID:Analysis of granulocyte colony stimulating factor receptor isoforms, polymorphisms and mutations in normal haemopoietic cells and acute myeloid leukaemia blasts. 865 69

To study acute myelogenous leukemia 1 (AML1) transcription factor, ETO protein, and t(8;21) AML chimeric AML1/ ETO protein in normal hematopoiesis and in leukemia, we raised rabbit antisera to a bacterially expressed polypeptide containing amino acid residues 1 to 220 of ETO and to synthetic peptides extending from residues 528 to 548 of ETO and 32 to 50 of AML1. The latter was selected to have little chance of cross-reactivity with other members of the PEBP2 alpha family. With affinity-purified reagents, we observed immunofluorescent staining for both AML1 and ETO in the nucleus of HEL, K562, and Kasumi-1 leukemic cell lines, the last from a t(8;21) AML. Biochemical analysis confirmed specificity of the antibodies and the nuclear localization of the antigens, the latter being exclusive for AML1 and primary for ETO. Immunoprecipitations of metabolically labeled 32P-proteins from Kasumi-1 cells show that AML1 and ETO are phosphorylated on serine and threonine. Investigations with normal bone marrow reveal AML1 and ETO are coexpressed in megakaryocytes and that each is expressed in a portion of the approximately 10-microns-diameter cells residing there. Using a CD34+ enriched population mobilized to peripheral blood, we found AML1 and, unexpectedly, ETO present in these cells. Because of this, we conclude that the expression of ETO in hematopoietic cells is not by itself leukemogenic. Also, because ETO would not be exclusively expressed as part of chimeric AML1/ETO in leukemic patients, its presence cannot be used to monitor t(8;21) AML residual disease.
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PMID:ETO and AML1 phosphoproteins are expressed in CD34+ hematopoietic progenitors: implications for t(8;21) leukemogenesis and monitoring residual disease. 878 39

MTG8 is a counterpart gene of AML1 in acute myeloid leukemia with t(8:21) translocation. Most of the coding region of the MTG8 is fused with AML1 runt domain. In normal tissues, the MTG8 is highly expressed in brain, but not in hematopoietic tissues. MTG8 may be important in leukemogenesis as well as in AML1 truncation. The function of MTG8 is assumed to be as a transcription factor, because it possesses several features common to transcription factors; putative zinc finger motifs, serine/threonine/proline-rich sequences and a region similar to TAF110. In this paper, we report on the protein properties of the MTG8.
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PMID:Significance of MTG8 in leukemogenesis. 920 71

A proto-oncogene, MTG8 (ETO/CDR), is disrupted in the t(8;21) translocation associated with acute myeloid leukemia, and the gene product, MTG8, is a phosphoprotein capable of cell transformation in concert with v-H-ras. To obtain insight into functional regulation of MTG8 by phosphorylation, we studied protein kinases that interact with, and phosphorylate, MTG8 in vitro. Recombinant MTG8 protein was first found to be associated with two serine/threonine protein kinases in cell extracts from both HEL cells and a leukemic cell line carrying t(8;21). A cytoplasmic protein kinase of 61 kDa (MTG8N-kinase) phosphorylated the amino-terminal of MTG8, and another of 52 kDa (MTG8C-kinase) phosphorylated the carboxyl-terminal domain. In addition, we demonstrated that heat shock protein 90 (HSP90) specifically binds to the amino-terminal domain of MTG8 in vitro and in vivo. Thus, our results shed new light on post-translational regulation of MTG8, perturbation of which, in AML1-MTG8 protein, probably contributes to leukemogenesis.
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PMID:Association of MTG8 (ETO/CDR), a leukemia-related protein, with serine/threonine protein kinases and heat shock protein HSP90 in human hematopoietic cell lines. 1007 66

Activity and expression of four major protein serine/threonine (Ser/Thr) phosphatases, protein phosphatase type 1 (PP1), protein phosphatase type 2A (PP2A), protein phosphatase type 2B (PP2B) and protein phosphatase type 2C (PP2C) were evaluated in normal peripheral leukocytes, and in various leukemic cells from patients with acute myelogenous leukemia (AML), common acute lymphocytic leukemia (cALL), or chronic lymphocytic leukemia (CLL). PP1 was the most abundant phosphatase in blood cells, and relative abundance of each phosphatase was: PP1 > PP2A > PP2B approximately = PP2C. PP1 activity and its expressions were higher in blasts of AML-M4 and -M5 than in cells of AML-M1, cALL and CLL. PP2A activity and its expression were higher in blasts of AML-M3, -M4 and -M5 than in cells of AML-M1, cALL and CLL. Activity and expression of both PP1 and PP2A in normal monocytes were highest, and PP2A activity in normal neutrophils was lowest among normal leukocytes. PP2B activity and its expression were higher in blasts of AML-M2, -M3 and normal lymphocytes. PP2C activity and its expression were relatively constant in various leukemic cell types. Activities of PP1 and PP2A of AML blasts correlated positively with the expression of CD11b, whereas activities of PP1 and PP2B correlated negatively with the expression of CD7. Thus, each phosphatase was ubiquitously but differently expressed in various leukemic cell types and in normal leukocytes. These data also suggest that expressions of PP1, PP2A and PP2B are relatively low in leukemic blasts arresting at the stage of early pluripotent stem cells, and are differently modulated during the course of myelomonocytic commitment and maturation.
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PMID:Expressions of four major protein Ser/Thr phosphatases in human primary leukemic cells. 1021 67

Vav and vav2 are members of the dbl family of guanine nucleotide exchange factors (GEF) for the rho/rac family of GTP binding proteins. Vav is expressed primarily in hematopoietic cells, while vav2 has a wider tissue distribution. The genomic structure of the human vav proto-oncogene was studied by identifying and sequencing all 27 exons of the gene from overlapping P1 and cosmid clones. The gene spans a 77-kb region on chromosome 19. In contrast, the coding region of vav2 is distributed over 30 exons spanning 227-kb. The overall organization of the exons which encode both proteins was found to be similar. In humans, alternative splicing of exons 6, 16 and 28 generated at least two distinct vav2 mRNA species. Several differences from the original vav cDNA sequence were noted. The most important difference was the identification of amino acid 718 as isoleucine, rather than threonine. This change warrants the reclassification of the vav SH2 domain as a type 3 SH2, instead of a type 2 SH2 as originally proposed by Songyang et al. (Mol. Cell. Biol. 14 (1994) 2777-2785). A series of vav promoter deletions were constructed using the enhanced green fluorescent protein (EGFP) as a reporter gene. A 23-bp segment that included a potential CBF/AML-1 binding site was found to be essential for EGFP expression in U937 cells. The same constructs were not active in HeLa cells, which do not express vav. A potential c-myb DNA binding site within the vav promoter was not required for EGFP expression.
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PMID:Genomic organization and regulation of the vav proto-oncogene. 1076 May 87


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