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)

The cell cycle phase-specific phosphorylation status of the RB protein (retinoblastoma tumor suppressor gene product) during an elicited cellular program of G0 arrest and cell differentiation was characterized. The RB protein phosphorylation state is presumed to be an important determinant of cell proliferation or arrest. The cell cycle phase specificity of RB protein phosphorylation and dephosphorylation during HL-60 human leukemia cell proliferation and differentiation was determined using DNA-based fluorescence-activated cell sorting and Western analysis. The RB protein in proliferating G1 cells was phosphorylated, but at a relatively low level. The extent of phosphorylation increased in S phase cells and was maximum in G2 + M cells. After the cells were treated with retinoic acid or 1,25-dihydroxy vitamin D3, they began to accumulate in G1/0 and phenotypically convert. Significant unphosphorylated RB protein did not appear until after the first cells had arrested and differentiated. Dephosphorylation of the RB protein was first apparent at the beginning of G2 in the remaining cycling cells after onset of arrest and differentiation had already occurred. By the time the remaining cycling cells had divided and arrested, resulting in G0 cells, a majority of RB protein was dephosphorylated, but some remained phosphorylated. The data indicate that dephosphorylation of RB does not determine residence in G1/0. Rather dephosphorylation appears as one relatively late-occurring component of the metabolic cascade culminating in G0-arrested, phenotypically differentiated cells. Dephosphorylated RB appears as a feature of differentiated cells. The data are consistent with a role for hypophosphorylated RB not so much in deriving, but in possibly sustaining the differentiated state.
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PMID:Late dephosphorylation of the RB protein in G2 during the process of induced cell differentiation. 808 28

The role of loss or inactivation of the retinoblastoma (Rb1) and p53 tumor suppressor genes in the pathogenesis of various human malignancies has been well established, yet little is known regarding plasma cell dyscrasias. In the present study, the loss of Rb1 protein expression, and the presence of Rb1 gene rearrangements as well as the presence of p53 somatic mutations (exons 5 through 9) were investigated in a panel of plasma cell dyscrasias, including 15 monoclonal gammopathies of undetermined significance (MGUS), 63 multiple myelomas (MM), and 18 plasma cell leukemias (PCL). In the same panel of cases, we established the frequency of ras oncogene mutations, the main genetic lesion associated with MM. We report that loss of Rb1 protein and p53 mutations are detectable in 34.7 and 9.8% of MM and PCL primary cases; no lesion was found in MGUS. In advanced stage MM, and PCL cases, Rb1 and p53 inactivation, as well as ras mutations were detected. Our findings show that Rb1 and p53 inactivation are associated with aggressive plasma cell dyscrasias, suggesting a role for these lesions in tumor progression rather than initiation.
Leukemia 1994 May
PMID:Inactivation of tumor suppressor genes, p53 and Rb1, in plasma cell dyscrasias. 818 33

Patients with a 47, XXY karyotype (Klinefelter syndrome) appear to have an increased risk of developing a malignancy in adulthood, usually cancer of the breast, extragonadal germ cell tumor, and acute nonlymphoblastic leukemia. There is growing evidence to show that these patients also have an increased risk of developing a malignancy in childhood. There are reports describing the development of acute lymphoblastic leukemia, retinoblastoma, and rhabdomyosarcoma in children with a 47, XXY or mosaic 47, XXY/46, XY karyotype. We report a child with a bone metastasizing, B-cell lineage, non-Hodgkin's lymphoma (NHL) who was found to have a 47, XXY karyotype in both the tumor and constitutional cells.
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PMID:Non-Hodgkin's lymphoma and Klinefelter syndrome. 820 45

We have shown that Tax1 of human T-cell leukemia virus type 1 stimulates the expression of several cellular immediate-early genes (M. Fujii, T. Niki, T. Mori, T. Matsuda, M. Matsui, N. Nomura, and M. Seiki, Oncogene 6:1023-1029, 1991). In this study, the 5'-flanking region of the human fra-1 gene, which is a Tax1-inducible fos-related gene, was isolated and Tax1 or serum-responsive cis elements were analyzed to obtain further insight into the mechanism of Tax1 action. The 62-bp sequence starting 46 nucleotides upstream from the translation initiation site showed 71% homology with the sequence surrounding the TATA box of the c-fos promoter. Regulatory motifs identified in the c-fos promoter, such as an Ets-binding site, E boxes, a CArG box, c-fos AP-1 sites, and two retinoblastoma control elements, were also found upstream of the c-fos homology region. A 502-bp fragment containing these motifs mediated transcriptional activation by Tax1 or by serum in a transient transfection assay. Three independent Tax1-responsive regions (TRRs) were identified, and mutations in each revealed that one of the retinoblastoma control elements in TRR1 and the c-fos AP-1 sites in TRR2 and TRR3 were essential for the activation. Although TRR2 contains a CArG box-like sequence, it was a weak binding site for p67SRF, if it bound at all, and was not required for activation. All three TRRs could also mediate the signals stimulated by serum. Thus, Tax1 appears to activate fra-1 gene expression by means of a part of the cellular machinery similar to that which mediates growth signals.
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PMID:Human T-cell leukemia virus type 1 Tax activates transcription of the human fra-1 gene through multiple cis elements responsive to transmembrane signals. 823 Apr 24

A 69-year-old woman presented with Rai stage 0 chronic lymphocytic leukemia. Ten years later she developed a diffuse centroblastic lymphoma involving the stomach. The surface membrane phenotype of the CLL cells was MD lambda while that of the large cell lymphoma (LCL) cells was MD kappa. The two populations had different heavy and kappa light chain rearrangements. Cytogenetic analysis of the CLL cells showed a deletion involving chromosome 13, band q14, but was unsuccessful in the LCL cells. However, use of a probe (p68 RS2.0) which recognizes a variable number tandem repeat sequence in the retinoblastoma gene, localized to chromosome 13q14, showed two alleles in the LCL cells but only one in the CLL cells. These data suggest that in this case of Richter's syndrome the CLL cells and the LCL cells are clonally distinct.
Leukemia 1993 Nov
PMID:Use of a retinoblastoma gene probe to investigate clonality in Richter's syndrome. 823 Dec 58

As the cure rate for childhood malignancies increases, the number of patients at risk for development of second malignancies also increases. Due to the potentially long remaining life span, long-term follow-up is difficult and patients are often at risk after presumptive cures. Some authors believe that cure rates for second malignancies are similar to cure rates for primary malignancies. We reviewed the records of 162 patients seen at our institution who had developed a second malignancy after treatment for childhood cancer. Presentation, age at diagnosis, tumor histology, extent of tumor, treatment (including radiotherapy with dosage when available, and chemotherapy) plus outcome were recorded. Mean age at diagnosis of the primary malignancy was 10.3 years. The most common primary malignancy was Hodgkin's disease (33) followed by soft tissue sarcoma (28), retinoblastoma (20), bone tumor (17), central nervous system (CNS) tumor (13), leukemia (8), Wilms' tumor (7), non-Hodgkin's lymphoma (6), neuroblastoma (5), thyroid neoplasm (5), and others (20). The average interval between diagnosis of the first and second malignancy was 10.8 years. These second tumors carried a high mortality. Only 56 patients have no evidence of disease. Five patients are known to be alive with disease and 92 patients have expired due to their second malignancy. Disease status in 8 patients is unknown. The most common second malignancy was osteosarcoma (35) followed by soft tissue sarcoma (24), breast cancer (15), leukemia (14), thyroid carcinoma (14), CNS tumors (12), melanoma (8), nonmelanomatous skin cancer (8), lymphoma (5), and others (27).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Forty-year experience with second malignancies after treatment of childhood cancer: analysis of outcome following the development of the second malignancy. 826 99

The retinoblastoma gene (RB) is a growth suppressor gene on the human chromosome 13q14. It encodes a 105 kDa phosphoprotein (p105), with DNA-binding capacity. P105 is thought to be involved in cell cycle control. Inactivation of RB is responsible for the development of retinoblastomas and occurs frequently in osteosarcomas and small cell lung cancer. In this study we looked at the RB-structure and expression in cell lines and primary lymphoma samples from patients with high grade non-Hodgkin's lymphoma (NHL). Forty five primary high grade NHL, the B-lymphoblastoid cell line IM-9 and the NHL cell line WSU-NHL were studied for RB structure by Southern blotting and for RB-expression by Northern blotting, Western blotting and immunocytochemistry. In all experiments freshly cryopreserved material was used. Southern and Northern experiments were performed with the 0.9 kb and 3.8 kb RB-cDNA probe. For the detection of p105 two different anti-p105-monoclonal antibodies were used in immunocytochemistry and Western blotting experiments. No RB mRNA and no p105 could be found in IM-9 cells. Twenty six high grade NHL samples (58%) showed no p105 expression. In the subgroup of centroblastic lymphomas 16 out of 21 and in Burkitt's lymphomas five out of eight showed no p105-expression. P105 expression is absent in 58% of high grade NHL, particularly in centroblastic and Burkitt's lymphomas, suggesting that inactivation of RB may play a crucial role in the pathogenesis of high grade NHL.
Leukemia 1994 Jan
PMID:Altered expression of the retinoblastoma gene product in human high grade non-Hodgkin's lymphomas. 828 6

While the incidence of cancer is increasing among both children and adults, mortality rates have decreased for children, while they have increased for adults. Of children diagnosed with cancer today, 80% are predicted to be long-term survivors. Although there are differences between children and adults with respect to the tumor types, biology, and outcome, there are common lessons which we can learn from our children regarding the genetics of cancer, its management and treatment, and the importance of longitudinal studies of the survivors. Specific pediatric cancers, such as retinoblastoma, have led to the recognition of tumor suppressor genes, now also observed among adult tumors including sarcomas, breast, lung, and bladder cancer. The presence of the tumor suppressor gene provides an understanding for the incidence of second malignant tumors among patients with heritable diseases. Furthermore, cancer prone families, such as those with the Li-Fraumeni syndrome, also carry the p 53 tumor suppressor gene; the presence of which greatly increases the risk of developing invasive cancer. Childhood cancer is rare; it represents only 1% of the total US cancer problem. However, 53% of all children with cancer, but only 2% of all adults, are studied via the NCI cooperative group mechanism. For some specific childhood tumors such as rhabdomyosarcoma and Wilms' tumor, as many as 70-85% of all cases are managed via NCI sponsored trials. Essentially all pediatric cancer is treated by interdigitating radiation with surgical resection and systemic chemotherapy. This approach has contributed to high cure rates. Finally, our understanding of the late effects of being a cancer survivor have come from longitudinal studies of children. The most severe long-term effects related to radiation in childhood pertain to growth and development, infertility, and second malignant tumor induction. Here the children treated for Hodgkin's disease have taught us the dose and volume effects on axial skeletal and soft tissue growth. Infertility issues are also treatment-related and may often be obviated by using gonadal shielding. The risk of secondary leukemia is related to dose and class of specific chemotherapeutic agents administered; it is 5.5% among children receiving 6 cycles of MOPP. There is a 22-fold risk at 30 years of age of solid tumor induction following radiotherapy for children with Hodgkin's disease. These serious concerns have been offset by current therapeutic approaches of using lower doses and smaller volumes of radiation with fewer cycles of less toxic chemotherapeutic agents. Childhood cancer ranks high among number of person-years of potential life saved annually.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Lessons from our children. 834 41

The phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), induced increased expression of the retinoblastoma (RB) tumor suppressor gene product in the course of megakaryocytic differentiation of the K562 human leukemia cell line, a differentiatively multipotent hematopoietic precursor cell. The induced increase in RB protein per cell occurred early, by 8 h of treatment, preceding any significant phenotypic differentiation evidenced by cellular expression of the CD41 differentiation-specific megakaryocytic cell surface marker, but not inhibition of cell cycle transit, leading to a cell population arrested with 2 n, 4 n, and 8 n DNA content. The increase in RB protein per cell occurred for cells in all cell cycle phases. Staurosporine (STSP) was found to induce a similar course of cell cycle arrest and differentiation. Furthermore, STSP caused an up-regulation of RB expression similar to that caused by TPA. Almost all of the RB protein is phosphorylated in untreated cells, but TPA and STSP both caused the late appearance of hypophosphorylated RB protein following cell cycle arrest. The STSP-caused hypophosphorylation was much later than the TPA effect. Hypophosphorylation of RB is, thus, not necessarily a prerequisite for cell cycle arrest but may be a consequence of G0. Given that TPA can be an activator and STSP an inhibitor of protein kinase C, it appears that the induced processes of tumor suppressor gene regulation and growth and differentiation control are not necessarily protein kinase C dependent in K562 cells. Furthermore, the findings that these two presumably divergent inducing agents caused a similar increase in RB gene expression suggests that the up-regulation of RB associated with differentiation is not a coincidence of just one specific inducer but may be a common essential feature of the induced differentiation. The amount of RB protein per cell increased within hours of exposure to TPA or STSP and may have a role in the induced metabolic cascade producing the new phenotype.
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PMID:12-O-tetradecanoylphorbol-13-acetate and staurosporine induce increased retinoblastoma tumor suppressor gene expression with megakaryocytic differentiation of leukemic cells. 836 61

We have previously shown that 30% of patients with B-cell chronic lymphocytic leukemia (B-CLL) have hemizygous deletions of the retinoblastoma (RB1) gene at 13q14. RB1 gene deletions may thus participate in malignant transformation of B-CLL, but it is also possible that a neighboring gene on 13q is the relevant one. To answer this question the remaining RB1 allele of eight clones with hemizygous deletions was studied by reverse transcription-polymerase chain reaction (RT-PCR), single-strand conformation polymorphism (SSCP) analysis, and immunofluorescense techniques. Cells from 10 patients without RB1 gene deletions were also studied by these methods. Lack of RB1 mRNA and RB protein expression was seen in leukemia cells from one of the patients. All other cases were found to be normal with regard to immunofluorescense, RT-PCR, and SSCP analysis, indicating at least one functional RB1 allele and supporting the importance of another gene in the 13q14 deletions. We then performed extended Southern blot analyses of the 13q region, using probes for 10 different loci. In 14 of 31 CLL clones (45%), deletions of a region telomeric to the RB1 gene (D13S25) were observed. In 4 of the cases the deletions were homozygous. Hemizygous deletions of the RB1 gene were observed in 11 of these patients and in none of the patients without D13S25 deletions. These data thus indicate that a gene(s) telomeric to RB1 is involved in the malignant transformation of CLL clones and that deletions of this region are a common event in this disease.
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PMID:Chronic lymphocytic leukemia cells with allelic deletions at 13q14 commonly have one intact RB1 gene: evidence for a role of an adjacent locus. 837 51


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