Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598766 (leukemogenesis)
 4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chromosomal findings are reported in three patients with acute myelomonocytic leukemia and in one with reticulosarcoma leukemia who had been treated for multiple myeloma with melphalan and X-ray. All four patients had striking chromosomal anomalies. An iatrogenic causation of aneuploidy is suggested. This is supported by chromosomal findings in patients with acute leukemia following polycythemia vera and Hodgkin's disease; practically all of the leukemias have been aneuploid. A comparison is made of such "secondary" acute leukemias with "primary" acute leukemias that are aneuploid in only 40% of the cases. Chromosomal changes are not considered to be the initial event in leukemogenesis.
Cancer Res 1975 Oct
PMID:Chromosome studies in acute leukemias developing in patients with multiple myeloma. 109 66

A single injection of Myleran reduced the pluripotent hematopoietic stem cell, i.e., colony forming unit(s) (CFU), and the erythropoietin-responsive cell (ERC) in polycythemic mice to around 0.5% that of the controls. Repeated injections of erythropoietin (EP) restored ERC populations, whereas the CFU remained at very low levels. This selective action of Myleran and EP in polycythemic mice seemed to be a good approach for the study of oncogenic action of Friend virus on target cells. When the CFU and ERC compartments were decreased, practically no response to the virus was obtained. When there was an appreciable ERC population present with decreased CFU, leukemogenesis still occurred (as judged by the increased spleen weight). This result was in proportion to the dose of EP, i.e., stimulation of the ERC or closely related cells.
J Natl Cancer Inst 1975 Aug
PMID:Target cell of the polycythemia-inducing Friend virus: studies with myleran. 115 25

The purpose of this study was to evaluate erythrokinetics and in vitro red blood cell (RBC) glucose utilization, 2,3-diphosphoglycerate production, and adenosine triphosphate levels following incubation in AKR mice from early in life until the onset of AKR lymphoma. Normal BALB/c mice served as controls. While hemoglobin concentration and RBC survival remained constant and similar in both groups of mice, the half disappearance time of injected radioactive 59Fe was longer and the 48-hr reappearance of 59Fe was less in AKR mice, compared with those of BALB/c mice. In vitro RBC metabolic studies indicated increased glucose utilization and 2,3-diphosphoglycerate production and decreased adenosine triphosphate levels following incubation in AKR RBC, in contrast to those in BALB/c RBC. RBC metabolic studies were also done in a small group of low leukemic C3H mice, and were similar to BALB/c mice. These differences became most marked in RBC from mice aged 15 to 30 weeks. Overt lymphoma began to occur after age 40 weeks. Hence, these erythropoietic changes occurred prior to the onset of lymphoma. The data imply a direct effect of virus infection on RBC or their precursors. The results are similar to changes in RBC metabolism noted in Rauscher-infected BALB/c mice. The broader implication of these findings in reference to viral host interactions and human leukemogenesis is discussed.
Cancer Res 1976 Jan
PMID:Red blood cell metabolism in AKR mice in the prelymphomatous phase. 124 99

Acute promyelocytic leukemia is a clonal expansion of malignant cells blocked at a specific stage of myeloid differentiation. The disease is associated with a specific translocation between chromosome 17 and chromosome 15 [t(15;17)] and with a bleeding diathesis previously attributed to disseminated intravascular coagulation, which has recently also been related to primary fibrinolysis. The high percentage of early deaths, about 20%, experienced by acute promyelocytic leukemia patients, is generally due to the hemorrhagic syndrome. A new finding is the high effectiveness of treatment with all-trans retinoic acid, a vitamin A derivative, for inducing complete remission. The induction of cellular maturation by this agent represents the first model of differentiation therapy. Furthermore, recent molecular studies revealed that the breakpoints of the t(15;17) translocation are clustered in the gene of retinoic acid receptor-alpha, generating a hybrid gene product. Gene transfection experiments disclosed the impairment of gene transactivation due to the hybrid gene products, opening new concepts for understanding leukemogenesis. Understanding the mechanisms of action of retinoic acid could extend differentiation therapy to other malignancies with aberrant gene transcription.
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PMID:Retinoic acid in acute promyelocytic leukemia: a model for differentiation therapy. 131 15

The acute promyelocytic leukemia 15;17 chromosomal translocation fuses the PML gene to the RAR alpha locus. The resulting chimeric gene encodes for a putative PML-RAR alpha fusion protein. PML is a putative transcriptional factor and RAR alpha is one of the nuclear retinoic acid receptors through which retinoic acid regulates gene expression. In this study, we investigated the retinoid binding and biochemical properties of the PML-RAR alpha protein by size exclusion high-performance liquid chromatography and immunoblot analysis and compared them with those of normal RAR alpha. The introduction of the expression vector PSG5/PML-RAR alpha into COS-1 cells led to high levels of expression of the PML-RAR alpha fusion protein. This protein was primarily localized in the nucleus and bound retinoids with the same affinity and specificity as the wild type RAR alpha receptor. The PML-RAR alpha fusion protein, but not the RAR alpha, was found in high molecular weight complexes with either itself or other nuclear factors. In the acute promyelocytic leukemia-derived cell line NB4, which contains the t(15;17) chromosomal marker, the PML-RAR alpha product was also found as a high molecular complex. The interaction of the PML-RAR alpha with itself or with other nuclear proteins may be important in understanding the role of the PML-RAR alpha fusion protein in promyelocytic leukemogenesis.
Cancer Res 1992 Jul 01
PMID:Characterization of the PML-RAR alpha chimeric product of the acute promyelocytic leukemia-specific t(15;17) translocation. 131 28

The frequent occurrence of TF gene involvement in translocations associated with leukemia is remarkable, although not yet explained. The wide variety of TFs involved in these translocations and the different stages of cellular maturation argue against a unifying mechanism. Recombinases, active during B-cell and T-cell development, have been implicated in gene arrangements involving TCR genes and in the SIL/SCL rearrangement, which involves two genes not normally rearranged. However, other mechanisms must clearly be active in generating these molecular abnormalities and perhaps they relate to the multistep maturation and differentiation processes and continuous cell turnover seen in hematopoietic cells. The difficulties in obtaining human solid tumor samples may make it more difficult to identify translocations involving TF genes in solid tumors. Recently, the cytogenetic analysis of solid tumors has improved and specific cytogenetic abnormalities have been associated with specific types of tumors. With advanced techniques, such as fluorescent in situ hybridization (a technique that does not depend on cell growth) and PCR, abnormalities involving TF genes will be discovered. Abnormalities of TF genes, other than translocations, have been seen in a broad variety of nonhematopoietic malignancies. The p53 protein has been shown to bind DNA in a sequence-specific fashion and interact with a variety of DNA tumor virus oncoproteins. The broad range of cell types that harbor p53 abnormalities suggests that TF abnormalities will likely be implicated in many solid tumors. We have detailed several examples of how gene rearrangements that accompany chromosomal translocations in acute leukemia can alter the expression or activity of cellular TFs. Several translocations generate fusion RNA transcripts and fusion TF proteins with altered functional characteristics. Other translocations result in the expression of a gene not normally detectable in hematopoietic cells or alter the level of its expression, or affect the promoter usage or exon structure of the gene (Table 2). Studies are underway in many laboratories to characterize the biologic activity of these abnormal TFs and it remains to be proven that these molecular abnormalities are directly linked with leukemogenesis. The identification of abnormal fusion transcripts and proteins may allow specific therapies to be directed against "tumor-specific" DNA, mRNA, or protein targets. Therapeutic strategies based on antisense or ribozyme technology may be used to turn off expression of these genes and inhibit leukemia cell growth. Immunologic methods can also be used to direct therapy against the malignant cells.
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PMID:Transcription factors, translocations, and leukemia. 136 70

We have previously cloned from K562 leukemia cells two novel fibroblast growth factor receptors (FGFR-3 and FGFR-4; J. Partanen et al., EMBO J., 10: 1347-1354, 1991). Here we have analyzed the mRNA expression of four different FGFRs, including the two novel genes in human leukemia cell lines. We show FGFR-1, FGFR-3, and FGFR-4 mRNAs in several leukemia cell lines at levels similar to those in solid tumor cell lines. Ligand cross-linking experiments indicate that K562 cells have receptors binding acidic FGF but not basic FGF. Expression of FGFRs in leukemia cells may reflect their presence on normal hematopoietic precursor cells or induction during leukemogenesis or cell culture.
Cancer Res 1992 Apr 01
PMID:Expression of fibroblast growth factor receptors in human leukemia cells. 137 35

This paper summarizes the clinical results achieved at the Milan Cancer Institute in advanced Hodgkin's disease through successive randomized studies performed during the last two decades. Long-term results confirm the therapeutic activity of a regimen containing bleomycin and doxorubicin, such as ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine), as salvage treatment and as primary chemotherapy, either when combined with radiation or cyclically alternated with MOPP (mechlorethamine/vincristine/procarbazine/prednisone). Delayed iatrogenic morbidity (namely, sterility and leukemogenesis) was less frequently documented in ABVD-treated patients compared with MOPP-treated patients. Nevertheless, bleomycin- and anthracycline-containing regimens can be refined in the attempt to further decrease iatrogenic toxicity.
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PMID:ABVD in the treatment of Hodgkin's disease. 138 43

In 43 cases of various B-cell lineage tumors, precise gene structures of rearranged immunoglobulin heavy chain (IgH) were studied. By Southern-blot analysis of D upstream (5'D) gene of IgH, biallelic rearrangement structures, D-J or V-D-J, were determined and consequently maturational stage specific IgH rearrangement patterns were investigated. B-precursor ALL cases (especially stage IV of Nadler's criteria) have V-D-J rearranged IgH genes on both alleles. In contrast, most of the mature B-cell malignancies, excluding multiple myeloma, have IgH genotype of D-J/V-D-J. In addition, in case of D-J/V-D-J, the D gene used in D-J joining has been speculated by Southern-blot of D genes. So, these approaches for inquiring precise structures of rearranged IgH genes are supposed to provide new information of lymphocyte differentiation and leukemogenesis.
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PMID:Maturational stage specific immunoglobulin heavy chain gene rearrangements, determined by D and D upstream region gene structures. 140 17

Point mutations in the p53 tumor-suppressor gene are the most frequently identified genetic alterations in human malignancies. In order to evaluate the role of p53 mutations in the multistep process of leukemogenesis we studied 61 patients with myelodysplastic syndromes using single-strand conformation polymorphism analysis of polymerase chain reaction products as well as direct sequencing. Mutant alleles were observed in 1/14 refractory anemia with excess of blasts (RAEB) and 2/5 RAEB in transformation. The three mutations represented G:C to A:T transitions at codon 141 (exon 5) and codons 245 and 248 (exon 7), respectively. These data suggest that p53 mutations may contribute, albeit rarely, to the development of preleukemic disorders of the myeloid cell lineage.
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PMID:P53 mutations in myelodysplastic syndromes. 145 75


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