Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study records the disease profile and outcome of all 492 children with confirmed cancer below the age of 15 who were admitted to Tygerberg Hospital, South Africa, from 1983 to 1993. The black (48.3%), so-called coloured (30.3%) and caucasian (21.3%) children did not represent a confined geographical area. Leukaemia (22.8%), brain tumours (20.5%), lymphomas (15.2%), nephroblastomas (10%), neuroblastomas (8.5%) and retinoblastomas (5.7%) were the most common tumours. All children were treated with standard protocols and included in the Kaplan-Meier survival analyses. 14 patients were lost to follow-up. Projected survival in (acute lymphoblastic leukaemia) ALL was 63% in white children, but only 17% in black children. Survival was 65% in stage 1 and 2 Wilms' tumour, and exceeded 50% in medulloblastoma and astrocytoma. So-called African Burkitt's lymphoma occurred in all population groups. Overall, 5-year survival in Hodgkin's disease was 70%. Black and coloured children with neuroblastoma presented mainly with stage 3 and 4 disease. All 26 black and coloured children with retinoblastoma had a negative family history and advanced disease which needed enucleation.
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PMID:The Tygerberg Hospital Children's Tumour Registry 1983-1993. 757 74

The cyclin-dependent kinase 4 (cdk4) inhibitor (p16INK4/MTS1/CDKN2) gene has been recently identified as a putative tumor suppressor gene because of the high frequency of homozygous deletion observed in numerous human tumor cell lines, including leukemias. However, results obtained from uncultured tumor samples have led to discussion of the relevance of these findings. Using reverse transcriptase polymerase chain reaction (RT-PCR) and Southern blot analysis, we have investigated p16INK4A gene at both RNA and genomic levels in various types of leukemias: acute myeloid leukemia (AML) (n = 23); acute lymphocytic leukemia (ALL) (n = 22) and B cell chronic lymphoproliferative disorders (CLPD) (n = 33). p16INK4A mRNA expression was not found in only 1/20 AML and 2/23 CLPD samples. Conversely, p16INK4A mRNA was not detected in 5/17 ALL cases, and intensity of PCR products were barely detectable in seven additional cases, possibly related to the contamination by normal cells in some cases. By Southern blotting, a homozygous deletion of p16INK4A gene was found in 6/17 ALL cases (35%) among which 4/6 were negative or weakly positive by RT-PCR assay. None of the five AML and 20 CLL samples studied had p16INK4A deletion. Sequence analysis of p16INK4A exon 2 did not show point mutation in two of these cases lacking mRNA expression. Our data provide further evidence that among hematological malignancies, ALL are the most likely to be associated with p16INK4A inactivation, mainly by homozygous gene deletion. Since most hematological malignancies-except ALL-are infrequently associated with p16INK4A and retinoblastoma (Rb) gene alteration it seems worthwhile to explore cdk4 and cdk6 expression to determine whether or not the disruption of the p16INK4A/Rb/cdk4/cdk6 regulatory loop might play a role in their pathogenesis.
Leukemia 1995 Jul
PMID:Alterations of cyclin-dependent kinase 4 inhibitor (p16INK4A/MTS1) gene structure and expression in acute lymphoblastic leukemias. 763 Jan 99

Experiments were performed to elucidate the mechanism through which p210 BCR-ABL, by its downstream signals, regulates c-myc messenger RNA expression in hematopoietic cells. We studied a model system in which stable expression of p210 BCR-ABL in interleukin-3 (IL-3) dependent murine myeloid cell lines led to growth factor independent transformation. Active c-myc transcription was observed in p210 BCR-ABL transformed cells by nuclear run-on assay, and in heterologous reporter assays performed with the 5' regulatory region of murine c-myc linked to firefly luciferase. Transcription initiation occurred primarily from the P2 promoter in p210 BCR-ABL transformed cells. Cis and trans elements responsible for transcription initiation from the c-myc P2 promoter were studied. Expression of E2F1 protein in p210 BCR-ABL transformed cells accounted, in part, for binding to the E2F site of the P2 c-myc promoter. The functional importance of E2F1 expression in p210 BCR-ABL transformed cells toward c-myc transcription was established in reporter assays performed with the P2 c-myc promoter containing either wild-type or mutant E2F sites. Mutation of the E2F motif of P2 5' c-myc reduced activity of the promoter by 50%. By gel mobility shift, E2F1 was found in P2 c-myc band shift complexes along with the cyclin-dependent kinase 2. Therefore, coupling of E2F to components of the retinoblastoma-cyclin pathway defines a route from p210 BCR-ABL to c-myc transcription, which is required for p210 BCR-ABL transformation.
Leukemia 1995 Sep
PMID:Role for E2F1 in p210 BCR-ABL downstream regulation of c-myc transcription initiation. Studies in murine myeloid cells. 765 19

The E2F transcription factor plays an important regulatory role in cell proliferation, mediating the expression of genes whose products are essential for inducing resting cells to enter the cell cycle and synthesize DNA. To investigate the possible involvement of E2F in hematopoietic malignancies, we isolated genomic clones encompassing the human E2F1 gene. We then used fluorescence in situ hybridization to localize E2F1 to human chromosome 20q11, telomeric to the p107 locus, a gene whose product is related to the retinoblastoma gene product (pRb). This finding contrasts with the 1p36 and 6q22 chromosomal locations previously assigned E2F2 and E2F3, two additional members of the E2F family. Although deletions or structural rearrangements of E2F1 were not detected in 14 primary acute leukemia or myelodysplasia samples with structural abnormalities of chromosome 20q11, the gene was amplified and overexpressed in HEL erythroleukemia cells and translocated to other chromosomes in several established human leukemia cell lines. This study provides the first evidence of gene amplification involving a member of the E2F family of transcription factors. We propose that E2F1 overexpression in erythroid progenitors may stimulate abnormal cell proliferation by overriding negative regulatory signals mediated by tumor suppressor proteins such as pRb.
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PMID:Amplification of the E2F1 transcription factor gene in the HEL erythroleukemia cell line. 777 10

The product of the human retinoblastoma gene (pRb) is a nuclear phosphoprotein that is thought to function as a tumor suppressor. Heterogeneous expression of the Rb gene product contributes to the genesis of a diverse group of human neoplasma such as breast, prostate, small cell lung, bladder carcinomas and leukemia. The clinical importance of Rb function demands a reproducible Rb immunohistochemical assay to distinguish Rb+ from Rb- tumor cells. We report an immunohistochemical study to detect Rb protein in a series of 50 invasive breast cancers. Our results support the hypothesis that the Rb gene functions as both a cell growth factor and a tumor suppressor.
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PMID:Expression of retinoblastoma protein in human breast cancer: an immunohistochemical study. 793 56

Blast cells from up to 70% of patients with acute myeloblastic leukemia (AML) exhibit a variable degree of autonomous growth in vitro which is related to the production of autocrine growth factors including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 (IL-1) and interleukin-6 (IL-6). Approximately 40% of AML blasts with autonomous growth have been reported to exhibit abnormalities of retinoblastoma (Rb) protein expression. As the Rb protein is a known transcriptional repressor of the IL-6 promoter, we have investigated the relationship between absence of Rb protein and cytokine gene expression in AML. Blasts from 28 patients were studied, 19 were Rb protein positive by Western blot and by flow cytometry for nuclear Rb protein; blasts from nine patients were Rb-negative. Of the 28 specimens tested by RT-PCR, 24 were positive for GM-CSF mRNA, 21 for IL-1 beta mRNA, and 14 for IL-6 mRNA. Only the expression of IL-6 was found to be significantly associated with loss of Rb protein expression (p < 0.02). The relationship between Rb protein and IL-6 expression was further studied by suppressing Rb protein expression with antisense oligonucleotides. In three out of seven blasts so treated, IL-6 mRNA was induced following antisense treatment whereas control sense oligonucleotides had no effect. Blasts from four patients which secreted high levels of IL-6 exhibited in vitro autonomous growth which could be partially suppressed by anti-IL-6. These results suggest that deletion of Rb protein expression is a mechanism that can dysregulate IL-6 expression in leukemic blasts and thus potentiate the autonomous growth of these cells.
Leukemia 1994 Nov
PMID:Absence of retinoblastoma protein expression results in autocrine production of interleukin-6 and promotes the autonomous growth of acute myeloid leukemia blast cells. 796 42

The relationship between the level of retinoblastoma protein (RB) expression and the survival of 113 newly diagnosed acute myelogenous leukemia (AML) patients was studied. Western blotting was used to determine the level of RB protein present in peripheral blood leukemia cells and results were confirmed in 26 patients by immunohistochemistry. The leukemic cells from 22/113 AML patients (19%) contained RB protein at levels that were equal to or less than the level of RB observed in the mononuclear cell fraction of peripheral blood from normal individuals (Low RB). Levels of RB greater than that of normal blood (Elevated RB) were seen in 91 patients (81%). The median survival of patients with low RB was significantly shorter than that seen in patients with elevated RB, 12 weeks versus 40 weeks (P = .02). Remission induction frequency was 36% in low RB patients compared with 68% in AML patients with elevated RB (P = .01). Multivariate analysis showed that low RB protein level was an independent prognostic factor predictive or poor survival after allowing for other known prognostic factors. These data suggest that a low level of the RB protein at the time of diagnosis is associated with shortened survival in AML patients because of inferior response to conventional therapy. Monitoring of the RB level could identify a subgroup of AML patients with an extremely poor prognosis when treated with chemotherapy alone, who would be eligible for alternative therapeutic strategies.
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PMID:Levels of retinoblastoma protein expression in newly diagnosed acute myelogenous leukemia. 801 20

Chromosome analysis of more than 1200 patients with chronic lymphocytic leukaemia reported to the International Working Party on Chromosomes in CLL and in the literature is analysed. Clonal chromosomal abnormalities are found in about half of the patients, and one third of those with clonal aberrations have trisomy 12, with or without additional changes. The most common structural abnormalities involve the long arm of chromosome 13, usually as deletions involving 13q14, the site of the retinoblastoma gene. Other recurrent abnormalities are deletions of the long arms of chromosome 11 and 6. 14q+ markers are frequent in patients at advanced stage, but are almost always within complex abnormalities. The number of clonal abnormalities in the CLL cells has a strong prognostic impact. Trisomy 12 as a single abnormality is an adverse prognostic sign, whereas patients with 13q abnormalities generally do comparatively well. Lymphoid leukaemia with monoclonal immunoglobulin secretion frequently involves clonal chromosomal abnormalities, and the type of change is similar to that seen in true CLL. In B cell prolymphocytic leukaemia, t(11;14) is a common finding, together with trisomy 12. T cell prolymphocytic leukaemia is characterized by an inversion of the long arm of chromosome 14, with breaks at q11 and q32, and trisomy of 8q, whereas large granular lymphocytic leukaemia has shown no consistent abnormality. Hairy cell leukaemia seems to involve a specific set of non-random chromosome abnormalities, such as inv(5)9.
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PMID:Cytogenetics in CLL and related disorders. 803 92

We have previously shown that blasts from some patients with acute myeloblastic leukaemia (AML) grow autonomously in vitro and that this growth pattern is related to the production of autocrine growth factors including granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-1 beta. However, another potential mechanism of autonomous growth involves the deletion of growth inhibitory molecules. One such inhibitory protein is the product of the retinoblastoma (Rb) gene which is expressed in normal haemopoietic cells and functions in cell cycle control and as a transcriptional repressor. Deletion of the Rb gene has been reported in various types of malignancy. We have examined the expression of the Rb gene product in blasts from 39 patients with AML by Western analysis. Using an antibody, Rb (Ab-2) which recognizes the C-terminal region, 11/39 samples (28%) failed to express Rb protein. The results of the Western blot analysis were confirmed by flow cytometry using a second antibody, Rb (Ab-1), against residues 300-380 of the Rb protein. Samples from seven of the 11 Rb-negative cases were studied for the expression of Rb mRNA; Rb mRNA was absent in four and three cases were positive. Analysis of the growth characteristics of these cells showed that blasts from 24/39 cases (62%) had partially or totally autonomous growth in a blast cell colony assay. Of these 24 samples with autonomous growth, 10 (41%) were Rb protein negative; in contrast, of the 15 cases with non-autocrine growth only one was Rb protein negative (7%, P < 0.05). Also, in Rb positive blasts, suppression of Rb protein production using an antisense oligonucleotide significantly increased proliferation of clonogenic AML blasts, confirming that the Rb protein acts as a negative regulator of growth in AML blasts. Our data suggest that deletion of Rb protein expression is frequently found in AML and is associated with the acquisition of autocrine growth characteristics, possibly as the consequence of derepression of genes involved in growth control and cytokine production.
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PMID:Decreased retinoblastoma protein expression in acute myeloblastic leukaemia is associated with the autonomous proliferation of clonogenic blasts. 804 35

Deletion of the retinoblastoma gene (Rb-1) was found in more than 50% (12/23) of patients with multiple myeloma (MM) by fluorescence in situ hybridization (FISH). Myeloma cells were highly purified from bone marrow aspirates by flow cytometry and analyzed using probes specific for the Rb-1 gene and the centromeric region of chromosomes 13 and 21. Routine cytogenetics revealed abnormal chromosome 13 in only 17% (4/23) of these patients. No correlation between Rb-1 deletion and tumor stage, immunoglobulin isotype, anemia, serum beta-2 microglobulin levels, patient age or the extent of prior therapy was found. However, the high incidence of Rb-1 deletion detected by FISH suggests a role of this tumor suppressor gene in the biology of MM. Although allelic loss of the Rb-1 gene is unlikely to be the only genetic change necessary for the development of MM, it may be a relatively early event in MM unrelated to chemotherapeutic intervention. Since the Rb-1 gene suppresses IL-6 production and secretion, Rb-1 deletion may result in deregulation of IL-6 expression and hence expansion of IL-6 dependent myeloma clones.
Leukemia 1994 Aug
PMID:Deletion of the retinoblastoma gene in multiple myeloma. 805 62


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