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)

The murine pim-1 gene, isolated as a locus frequently activated by proviral integration in T cell lymphomas, encodes a protein serine kinase. Although genetic evidence suggests a crucial role for this protooncogene in cell growth and transformation, very little is known about its protein product. The murine pim-1 mRNA provides alternate translational starts at a CUG codon +87-89 and an AUG codon at +339-341, in the same open reading frame (ORF), resulting in 44-kDa (397 amino acids) and 34-kDa (313 amino acids) isoforms. In this report, we demonstrate that the human PIM-1 mRNA is translated only from the single initiation methionine codon at +339-341 under cell-free conditions. Immunoblotting analyses of several human solid tumor cell lines, with highly specific antisera reveal two ubiquitously expressed isoforms (35 and 34 kDa). The estimated half-life of these proteins is shorter in the normal peripheral blood leukocytes (<5 min) than in the chronic myelogenous leukemia cells K562 (<20 min). Immunoblotting analyses of centrifugally elutriated fractions of the chronic myelogenous leukemia BV173 cells demonstrate that the levels of PIM-1 increase during the progression from early to late GI, remain high at the G1/S boundary and G2 phases of the cell cycle. The results presented here suggest a ubiquitous role for PIM-1 in progression through cell cycle.
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PMID:Ubiquitous expression and cell cycle regulation of the protein kinase PIM-1. 866 Jun 54

Granulocytic sarcoma or chloroma is defined as an extramedullary solid tumor, composed of granulocytic precursor cells at various levels of differentiation. Granulocytic sarcoma is mostly associated with acute and chronic leukemia, rarely with polycythemia vera and myelofibrosis. The use of special immuno-histochemical stains is mandatory, because this tumor is often misdiagnosed as malignant lymphoma. We report two cases of granulocytic sarcoma (tonsil and ovary) associated with chronic myelogenous leukemia. We describe the first reported association of atypical CML and granulocytic sarcoma.
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PMID:Granulocytic sarcoma (chloroma): a report of two cases. 869 67

DR-nm23 cDNA was cloned recently by differential screening of a cDNA library derived from chronic myelogenous leukemia-blast crisis primary cells. It is highly homologous to the putative metastasis suppressor nm23-H1 gene and the closely related nm23-H2 gene. When overexpressed in the myeloid precursor 32Dcl3 cell line, it inhibited granulocyte colony-stimulating factor-stimulated granulocytic differentiation and induced apoptosis. We have now found that the expression of DR-nm23 is not restricted to hematopoietic cells but is also detected in an array of solid tumor cell lines, including carcinoma of the breast, colon, and prostate, as well as the glioblastoma cell line T98G. We have also isolated both the gene and its 5'-flanking region and found that DR-nm23 localizes on chromosome 16q13. The gene consists of six exons and five introns. When fused in-frame to the nucleotide sequence for the green fluorescent protein and transfected in SAOS-2 cells, it generates a protein of the predicted size that localizes to the cytoplasm. The 5'-flanking region of DR-nm23 does not contain a canonical TATA box or a CAAT box, but it is G+C rich and contains two binding sites for the developmentally regulated transcription factor activator protein 2 (AP-2). Transient expression assays of DR-nm23 promoter-chloramphenicol acetyltransferase constructs demonstrated that the segment from nucleotides -1028 to +123 has the highest activity in hematopoietic K562 cells and in TK-ts13 hamster fibroblasts. Moreover, AP-2 induced a 3-fold transactivation of the DR-nm23 5'-flanking segment from nucleotides -1676 to +123 and interacted specifically with oligomers containing putative AP-2 binding sites (-936 to -909, and -548 to -519) as indicated by electrophoretic mobility shift assay. Furthermore, nuclear run-on assays from high and low DR-nm23-expressing cells (K562 and CCRF-CEM, respectively) revealed similar transcription rates. Therefore, the regulation of the DR-nm23 gene expression might involve other mechanisms occurring at posttranscriptional and/or translational levels.
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PMID:Gene structure, promoter activity, and chromosomal location of the DR-nm23 gene, a related member of the nm23 gene family. 906 90

Cytogenetic aberrations resulting in deletion of 3p are common in solid tumors, indicating the presence of tumor suppressor genes (TSG) on this chromosome arm. The present study was undertaken to investigate 3p loss in hematologic disorders. Ten acute myeloid leukemias (AML), two myelodysplastic syndromes (MDS), one Philadelphia chromosome-positive chronic myeloid leukemia (CML), three acute lymphoblastic leukemias (ALL), one chronic lymphoproliferative disorder (CLD), and three non-Hodgkin's lymphomas (NHL) with abnormalities leading to 3p deletions were identified, constituting 2.9% of AML, 0.7% of MDS, 1.0% of CML with changes in addition to t(9;22), 1.5% of ALL, 4.2% of CLD, and 1.1% of NHL with cytogenetic abnormalities analyzed at our Department. Among 19042 karyotypically aberrant published cases, 1.2% of 6260 AML, 1.3% of 2285 MDS, 0.8% of 840 chronic myeloproliferative disorders (CMD), 0.7% of 1894 CML with additional aberrations to t(9;22), 0.6% of 3589 ALL 2.4% of 1602 CLD, 4.5% of 178 Hodgkin disease (HD), and 3.1% of 2394 NHL displayed partial loss of 3p (0.6-4.5%; P < 0.001); the majority occurring together with other abnormalities. The frequencies of 3p loss did not differ significantly among the MDS, ALL, and CLD morphologic subgroups, between B and T cell ALL, CLD, and NHL, among low-, intermediate-, and high-grade NHL, or between therapy-related MDS and de novo MDS, whereas the incidence of 3p deletions was higher in treatment-associated AML (P < 0.001) than in de novo AML and varied among the AML FAB groups (P < 0.001). The most frequently deleted chromosome bands were 3p25 in AML, 3p26 in MDS, 3p14 in CMD, 3p25, 3p23, and 3p21 in CML, 3p26 and 3p25 in ALL, 3p26 and 3p25 in CLD, 3p26 in HD, and 3p26 in NHL. These deletion hot spots are more distal than those reported in most solid tumor types, suggesting that different TSG are involved in hematologic malignancies and solid neoplasms.
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PMID:Deletion of chromosome arm 3p in hematologic malignancies. 926 71

Cancer incidence and mortality data from the atomic bomb survivors cohort has been analyzed to allow for the possibility of a threshold dose response. The same dose-response models as used in the original papers were fit to the data. The estimated cancer incidence from the fitted models over-predicted the observed cancer incidence in the lowest exposure group. This is consistent with a threshold or non-linear dose-response at low-doses. Thresholds were added to the dose-response models and the range of possible thresholds is shown for both solid tumor cancers as well as the different leukemia types. This analysis suggests that the A-bomb cancer incidence data agree more with a threshold or non-linear dose-response model than a purely linear model although the linear model is statistically equivalent. This observation is not found with the mortality data. For both the incidence data and the mortality data the addition of a threshold term significantly improves the fit to the linear or linear-quadratic dose response for both total leukemias and also for the leukemia subtypes of ALL, AML, and CML.
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PMID:Threshold models in radiation carcinogenesis. 1008 7

Between 1995 and 1997 twenty two patients with different hematological diseases ( CML n=10, AML n=6, ALL n=l, NHL n=3, SAA n=1,solid tumor n=1 ) and a median age of 37 (range, 20 to 55) years received unmanipulated peripheral blood stem cell (PBSC) transplants from HLA-identical sibling donors at our institution. Myeloablative chemotherapy consisted of cyclophosphamide (CY) and total body irradiation in 11, and chemotherapy alone in 11 patients. For graft-versus host-disease (GVHD) prophylaxis all patients were given cyclosporine A and methotrexate according to the Seattle protocol. PBSC were mobilized by granulocyte colony-stimulating factor (G-CSF) given at 10 microg/kg body weight (b.w.)/day for four days. Harvest of PBSC was started on day 5 and continued on day 6 if necessary. A median of 1 leukapheresis (range, 1 to 2) was performed and a median of 5.7 x 10(6) CD34+cells/kg b.w. (1.34 to 21.5) were obtained. Ten patients received G-CSF (5 microg/kg b.w.) starting on day one after PBSCT until neutrophil recovery. Absolute neutrophil counts >0.5 x 10(9)/L and ANC >1.0 x 10(9)/L were reached after a median of 13 (range 8 to 18) and 15 (range 9 to 19) days after PBSCT. Unsupported platelet counts >20 x 10(9)/L and 50 x 10(9)/L were reached after 17 (range 8 to 32) and 22 (range 13 to 40) days after PBSCT, respectively. Incidence of acute GVHD grade I to IV was 52%, extensive chronic GVHD occurred in 25% of patients. After a median observation time of 11 (range, 3 to 34) months twelve patients (55%) are alive and well. In summary, infusion of allogeneic PBSC after myeloablative therapy allows rapid and sustained hematologic reconstitution. Incidence of acute GVHD is not increased, for assessment of chronic GVHD longer observation times and larger patient numbers are required.
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PMID:Experience with allogeneic and syngeneic blood stem cell transplantation in patients with hematological malignancies. 991 35

The product of the Wilms' tumor gene WT1 is a transcription factor overexpressed not only in leukemic blast cells of almost all patients with acute myeloid leukemia, acute lymphoid leukemia, and chronic myeloid leukemia, but also in various types of solid tumor cells. Thus, it is suggested that the WT1 gene plays an important role in both leukemogenesis and tumorigenesis. Here we tested the potential of WT1 to serve as a target for immunotherapy against leukemia and solid tumors. Four 9-mer WT1 peptides that contain HLA-A2.1-binding anchor motifs were synthesized. Two of them, Db126 and WH187, were determined to bind to HLA-A2.1 molecules in a binding assay using transporter associated with antigen processing-deficient T2 cells. Peripheral blood mononuclear cells from an HLA-A2.1-positive healthy donor were repeatedly sensitized in vitro with T2 cells pulsed with each of these two WT1 peptides, and CD8(+) cytotoxic T lymphocytes (CTLs) that specifically lyse WT1 peptide-pulsed T2 cells in an HLA-A2.1-restricted fashion were induced. The CTLs also exerted specific lysis against WT1-expressing, HLA-A2.1-positive leukemia cells, but not against WT1-expressing, HLA-A2.1-negative leukemia cells, or WT1-nonexpressing, HLA-A2. 1-positive B-lymphoblastoid cells. These data provide the first evidence of human CTL responses specific for the WT1 peptides, and provide a rationale for developing WT1 peptide-based adoptive T-cell therapy and vaccination against leukemia and solid tumors.
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PMID:Human cytotoxic T-lymphocyte responses specific for peptides of the wild-type Wilms' tumor gene (WT1 ) product. 1066 72

Calpain is a calcium-dependent cysteine protease that is implicated in calcium-dependent cell death, and calpain inhibitors are generally considered as inhibitors of apoptosis. To the contrary, in the present study, we found that calpain inhibitor II (CPI-2) triggers rapid apoptosis in acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) cells. All target cell lines were killed by CPI-2, including: ALL-1, a multidrug-resistant BCR-ABL fusion transcript-positive t(9;22) pro-B ALL cell line; RS4;11, a highly radiation-resistant MLL-AF4 fusion transcript-positive t(4;11) pre-pre B ALL cell line; RAMOS, a highly radiation-resistant and p53-deficient Burkitt's lymphoma cell line; DAUDI, a Burkitt's leukemia/lymphoma cell line; NALM-6, a pre-B ALL cell line; and JURKAT and MOLT-3, two T-lineage ALL/NHL cell lines. CPI-2-induced apoptosis in LYN-deficient and BTK-deficient subclones of the DT-40 lymphoma B cell line as effectively as it did in wild-type DT-40 cells. Thus, CPI-2-induced apoptosis is not dependent on the protein tyrosine kinases LYN or BTK. Notably, caspase inhibitor I effectively inhibited CPI-2-induced apoptosis, suggesting that the inhibition of a CPI-2-susceptible protease results in caspase activation, leading to apoptosis in ALL/NHL cells. Unlike the high calpain-expressing ALL/NHL cell lines, myeloid leukemia cell lines HL-60/AML, K562/CML, and U937/AMML, or solid tumor cell lines BT-20/breast cancer, PC-3/prostate cancer, U373/glioblastoma, and HeLa/epitheloid cancer, were not susceptible to the cytotoxicity of CPI-2. Taken together, our results identify calpain as a new molecular target for the treatment of ALL and NHL. CPI-2 and its analogues represent a promising new class of antileukemia/lymphoma agents that deserves further development.
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PMID:Calpain inhibitor II induces caspase-dependent apoptosis in human acute lymphoblastic leukemia and non-Hodgkin's lymphoma cells as well as some solid tumor cells. 1087 99

This report describes a tumor-associated antigen, termed CML66, initially cloned from a chronic myelogenous leukemia (CML) cDNA expression library. CML66 encodes a 583-aa protein with a molecular mass of 66 kDa and no significant homology to other known genes. CML66 gene is localized to human chromosome 8q23, but the function of this gene is unknown. CML66 is expressed in leukemias and a variety of solid tumor cell lines. When examined by Northern blot, expression in normal tissues was restricted to testis and heart, and no expression was found in hematopoietic tissues. When examined by quantitative reverse transcription-PCR, expression in CML cells was 1.5-fold higher than in normal peripheral blood mononuclear cells. The presence of CML66-specific antibody in patient serum was confirmed by Western blot and the development of high titer IgG antibody specific for CML66 correlated with immune induced remission of CML in a patient who received infusion of normal donor lymphocytes for treatment of relapse. CML66 antibody also was found in sera from 18-38% of patients with lung cancer, melanoma, and prostate cancer. These findings suggest that CML66 may be immunogenic in a wide variety of malignancies and may be a target for antigen-specific immunotherapy.
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PMID:CML66, a broadly immunogenic tumor antigen, elicits a humoral immune response associated with remission of chronic myelogenous leukemia. 1141 19

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. These tumors span a wide clinical spectrum from benign to malignant and have long been recognized for their nearly absolute resistance to chemotherapy and radiation treatment. Surgery is the primary treatment modality for GISTs, but GISTs represent an incurable malignancy for patients with metastatic or unresectable disease. Thus, novel approaches to the treatment of GISTs were desperately needed. Gastrointestinal stromal tumors are characterized by expression of the transmembrane receptor tyrosine kinase KIT, which is defined by the CD117 antigen and is the product of the c-kit proto-oncogene. Activating or gain-of-function mutations in the c-kit gene have been identified in the majority of GIST cases. The resulting constitutive KIT tyrosine kinase activity was hypothesized to provide growth and survival signals to GIST cells and to be crucial to the pathogenesis of the disease. This hypothesis became testable with the identification of the signal transduction inhibitor imatinib mesylate (formerly STI571, [Gleevec]; Novartis Pharmaceuticals Corp, East Hanover, NJ), which blocks the tyrosine kinase activity of KIT as well as the kinase activity of the normal c-abl gene product, the oncogenic Bcr-Abl chimeric fusion protein of chronic myeloid leukemia, and the platelet-derived growth factor receptor. Preclinical experiments showed rapid inhibition of ligand-independent KIT phosphorylation, decreased cellular proliferation, and induction of apoptosis after exposure of GIST cells to imatinib mesylate in vitro. These results provided the rationale to move forward with clinical testing of imatinib mesylate as an anticancer therapy for GIST. In early 2000, a dramatic clinical and radiographic response to imatinib mesylate was shown in a single patient with advanced, chemotherapy-resistant GIST. The powerful scientific rationale for this proof-of-concept study, together with the durable and significant response observed in this first GIST patient treated with imatinib mesylate, have provided the driving force for rapid clinical development of this targeted therapy in this solid tumor indication.
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PMID:Targeting c-kit mutations in solid tumors: scientific rationale and novel therapeutic options. 1174 Aug 3


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