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Query: UMLS:C0598766 (leukemogenesis)
 4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Murine radiation-induced acute myeloid leukemia (RI-AML) may be considered as the experimental counterpart of human secondary leukemia. Three new myelomonocytic cell lines derived from RI-AML and carrying a partially deleted chromosome 2 are described. The RI-AML cells responded with increased proliferation after being incubated with the hemopoietic growth factors rG-CSF, rGM-CSF and IL-3. Increased proliferation of the same extent without any effect in differentiation, was also demonstrated in the RI-AML cells after incubation with IL-6 and with mouse lung conditioned medium (CM) and Krebs ascites tumor cells CM which induce differentiation in normal and most leukemic myeloid cells. Down-regulation of the c-myc gene and induction of (2'-5') oligo-adenylate synthetase (reflecting autocrine interferon secretion), two essential mechanisms operating during arrest of growth and concomitant differentiation, were demonstrated to be absent in RI-AML cells. In contrast, the M1 cells responded to the above differentiating factors with growth arrest and differentiation and with appropriate c-myc down-regulation and synthetase induction. The genetic basis for the distinct RI-AML cells' behavior may be connected with the loss or structural and/or functional abnormalities of DNA sequences located in the deleted part of chromosome 2 or in the respective allele. The presently described new RI-AML cell lines may be used for studies concerning myeloid leukemogenesis in general and secondary leukemia in particular.
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PMID:Absence of negative growth regulation in three new murine radiation-induced myeloid leukemia cell lines with deletion of chromosome 2. 145 74

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

We report a new, nonrandom t(2;16)(p11.2;p11.2) in childhood acute lymphoblastic leukemia (ALL). Three of 292 patients with childhood ALL studied at Indiana University Medical Center had this translocation. All three had additional chromosomal abnormalities at diagnosis and were classified as having low hyperdiploidy (47-49 chromosomes) with structural abnormalities. The patients, two boys and one girl, ranged in age from 3 to 13 years. Peripheral white blood cells (WBC) counts ranged from 1.8 to 107.4 x 10(9)/L, all were classified as French-American-British (FAB) type L1, and all had B-lineage ALL. Because all three patients have relapsed after first remissions of 2 years 8 months to 6 years, the t(2;16) may indicate a poor prognosis and more aggressive treatment may be indicated for such patients. Because this translocation was the sole abnormality in one clone of patient 2 at relapse, it may be considered the primary abnormality. Therefore, it may also be the primary abnormality in the other two patients, and the genes involved in the breakpoints may be important in leukemogenesis.
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PMID:A new nonrandom chromosomal abnormality, t(2;16)(p11.2;p11.2), possibly associated with poor outcome in childhood acute lymphoblastic leukemia. 145 51

This is the first report in Israel of the successful treatment of acute promyelocytic leukemia (APL; M3) with an active metabolite of vitamin A. In a 42-year-old woman with APL all-trans-retinoic acid (ATRA; tretinoin), 45 mg/m2/day was given per os for 90 days. APL is associated with a distinct cytogenetic abnormality: translocation of a portion of the long arm chromosome 17 onto the long arm chromosome 15t (15; 17) with a breakpoint on chromosome 17 in the region of the retinoic acid receptor-alpha (RAR-alpha), playing a crucial role in the leukemogenesis of APL. In man, the drug induces myeloid and mainly promyelocytic leukemic cells to differentiate, without the development of bone marrow hypoplasia. In our patient it caused complete remission and the disappearance of intravascular disseminated coagulation. The only side-effects were a transient macular rash, gastrointestinal symptoms and mild hypertriglyceridemia. Other principal adverse effects reported in the literature are relatively not very serious and consist of dryness of the skin, occasional headaches and intracranial hypertension, nasal congestion, lymphadenopathy, respiratory distress with infiltrates in the lung, bone pain and increased hepatic aminotransferase. A hyperleukocytosis syndrome seems to be more problematic. ATRA appears to be superior to conventional chemotherapeutic regimens. It is safe and highly effective in inducing clinical, morphologic and karyotypic remission with a marked decrease in the expression of the abnormal RAR-message in APL. There is a possible molecular link between the pathogenesis and treatment of this severe and often fatal coagulopathic disease. This therapy of course does not eradicate the leukemic clone, and consolidation chemotherapy or bone marrow transplantation is necessary.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Remission of acute promyelocytic leukemia after all-trans-retinoic acid]. 148 98

Virtually all cases of childhood acute lymphoblastic leukemia have chromosomal abnormalities. Non-random chromosomal abnormalities have been correlated with leukemic cell lineage, the degree of cell differentiation and certain clinical and biologic features. Cytogenetic findings have prognostic significance, but the adverse influence of many rearrangements, including most chromosomal translocations, may be offset by the greater cytoreductive effects of intensified therapy. Cytogenetic abnormalities have also provided focus for molecular studies of leukemogenesis. Such studies have recently identified key genes and their protein products which play important roles in malignant transformation and proliferation.
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PMID:Cytogenetic abnormalities in childhood acute lymphoblastic leukemia correlates with clinical features and treatment outcome. 149 25

Oncogenic conversion of transcription factors by chromosomal translocations is implicated in leukemogenesis. We report that the t(17;19) in acute lymphoblastic leukemia produces a chimeric transcription factor consisting of the amino-terminal portion of HLH proteins E12/E47 (products of the E2A gene) fused to the basic DNA-binding and leucine zipper dimerization motifs of a novel hepatic protein called hepatic leukemia factor (Hlf). Hlf, which is not normally transcribed in lymphoid cells, belongs to the recently described PAR subfamily of basic leucine zipper (bZIP) proteins, which also includes Dbp and Tef/Vbp. Wild-type Hlf is able to bind DNA specifically as a homodimer or as a heterodimer with other PAR factors. Structural alterations of the E2a-Hlf fusion protein markedly impair its ability to bind DNA as a homodimer compared with wild-type Hlf. However, E2a-Hlf can bind DNA as a heterodimer with other PAR proteins, suggesting a novel mechanism for leukemogenic conversion of a bZIP transcription factor.
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PMID:Hlf, a novel hepatic bZIP protein, shows altered DNA-binding properties following fusion to E2A in t(17;19) acute lymphoblastic leukemia. 151 26

The activation of protooncogenes (ras, fms and myc genes) by point mutations in hematological malignancies are described in this review. Ras mutations are found in a variety of human malignancies at codon 12, 13, and 61. Generally, N-ras mutations are frequent in hematological malignancies. Fms mutation at codon 301 and 969, which are seen in 10 to 20% cases of AML and MDS, increase tyrosine kinase activity of the fms products. Ras and fms mutations are postulated to influence leukemogenesis at rather early stages. Burkitt lymphomas are characterized by specific chromosomal translocations between c-myc gene and one of the immunoglobulin genes. Furthermore, mutations in the 3' border of the exon 1 of c-myc are frequent, and may play an additional role in pathogenesis of Burkitt lymphoma.
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PMID:[Activation of protooncogenes by point mutations in hematological malignancies]. 151 54

The deleted in colorectal carcinomas (DCC) gene, located in human chromosome band 18q21, was identified as a potential tumor suppressor gene by Fearon et al. in 1990. The DCC gene encodes a protein which is highly similar to neural cell adhesion molecules and other related cell surface glycoproteins. In colorectal carcinoma, the expression of the DCC gene is reduced or absent in 88% of cases. We examined the expression of the DCC gene using reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Its expression was reduced or absent in some leukemias. Our findings suggest the possibility that this gene may play a role in leukemogenesis.
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PMID:[DCC gene and leukemia]. 151 58

Gamma-irradiation of plateau phase cultures of the clonal murine bone marrow stromal cell line D2XRII followed by cocultivation of a clonal interleukin 3 (IL-3) (granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent hematopoietic progenitor cell line FDC-P1JL26 results in a significant increase in "cobblestone islands" of attachment and emergence of subclonal factor-independent malignant sublines. Biochemical purification of conditioned medium from irradiated D2XRII cells yielded a 75,000-dalton glycoprotein termed leukemogenic stromal factor (LSF) that was neutralized by a polyclonal antiserum to murine macrophage colony-stimulating factor (M-CSF). A monoclonal antibody to the murine M-CSF receptor (c-fms) neutralized the biological activity of this molecule in a manner comparable to its effect on recombinant human or murine M-CSF. FDC-P1JL26 parent cells were positive for Ly5, MEL-14, mGR, VLA-4, PGP-1 (CD44), and Thy1.2. After culture in LSF, Thy1.2, MEL-14, and mGR became undetectable; however, significant cell surface MAC-1 antigen and c-fms (M-CSF receptor) were expressed. Neither line was positive for Ly6, Ly22, I-CAM-1, or B220 antigen. LSF-precultured FDC-P1JL26 cells transferred as single cells to microwell culture with 5000-cGy-irradiated D2XRII cells revealed a 60-fold increase in frequency of cobblestone island formation and evolution of factor-independent subclones compared to the parent line. Both parent and LSF-precultured cells became factor independent at a 100-fold lower frequency if kept in suspension in LSF in the absence of stromal cells. Antiserum to M-CSF or monoclonal antibody to the murine M-CSF receptor (c-fms) did not inhibit or displace cobblestone island formation by either clone of FDC-P1 on irradiated stromal cells indicating a mechanism of binding not involving the M-CSF receptor. However, anti-serum to the M-CSF receptor inhibited growth of one factor-independent subclone. In separate studies, a subclone of IL-3-dependent 32Dc13 cells, expressing the transfected murine c-fms protooncogene but not the parent 32Dc13 cell line or another subclone expressing the transfected gene for the human M-CSF receptor, showed adherence and became factor independent when cocultivated with irradiated D2XRII stromal cells. Thus, irradiated stromal cells bind M-CSF receptor-positive hematopoietic progenitor cells and induce c-fms-dependent factor-independent tumorigenic subclones. The cellular interactions in this model may be relevant to gamma-irradiation leukemogenesis in vivo.
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PMID:Humoral and cell surface interactions during gamma-irradiation leukemogenesis in vitro. 153 94

Two cases of acute myeloblastic leukemia (AML M2) associated with a deletion of chromosome 6q are described. One was a 38-year-old man with constitutional inversion of chromosome 9, and another was a 57-year-old female atomic-bomb survivor. The karyotype of these patients were 46,XY,del(6)(q12q14),inv(9)(p11q13), and 47,XX,6q-,+min, respectively. In both cases c-myb protooncogene, which is located in chromosome 6q, was neither deleted nor rearranged, and c-myb messenger RNA level was not elevated. These results suggest that c-myb is not involved in the leukemogenesis of AML with 6q- as well as lymphoid malignancies with 6q-. Out of 23 AML cases with 6q- reviewed, 6 cases had erythroleukemia, and 4 developed in Down syndrome patients.
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PMID:Deletion of chromosome 6q in two cases of acute myeloblastic leukemia and a review of the literature. 155 Oct 86


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