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

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

To clarify the idea that an alteration of the transferrin receptor (TF-R) gene, localized to 3q26, may be of pathogenetic significance in hematological disorders with 3q anomaly, we studied the TF-R systems of erythroblasts from both functional and genetic aspects. The patient described here had refractory anemia with an excess of blasts (RAEB), with paracentric inversion, inv(3)(q21q26). The patient had the characteristic findings of micromegakaryocytosis and thrombocytosis, with giant platelets. There was no functional abnormality of TF-R as far as number of binding sites, affinity, molecular weight, or recycling kinetics were concerned. Furthermore, we could not recognize any rearrangement of the TF-R gene with Southern blot analysis. These data suggest that TF-R is not involved in the pathogenesis of leukemogenesis and thrombocytosis of the disease.
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PMID:The transferrin receptor system is not involved in the pathogenesis of hematological disorders with 3q inversion. 230 80

Certain hematopoietic disorders and immunodeficiency states are known to carry a risk of developing acute nonlymphocytic leukemia. In the past some of them have been classified by a variety of terms ranging from refractory anemia to preleukemia, but are currently grouped into a new concept of the myelodysplastic syndromes (MDS). The purpose of this article is to briefly review the updated knowledge of the MDS with emphasis on the clonal origin, natural history and mechanisms of leukemogenesis.
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PMID:[Preleukemic disorders]. 264 30

Administration of aggressive chemotherapy to patients with cancer has considerably improved their outlook for effective palliation or cure. However, a hitherto unappreciated complication consisting of a secondary malignancy, in particular acute leukemia, has emerged. Prolonged therapy with alkylating agents and chemotherapy plus radiotherapy are associated with an increased risk of this complication. The disease evolves through a preleukemic phase of pancytopenia and sideroblastic refractory anemia. The median onset from the initiation of chemotherapy is about 5 years with an increasing incidence with time. Myelomonocytic, monocytic and erythroleukemia with atypical features and resistance to conventional therapy predominate. Hyploidy and aberrations involving chromosomes 5 and 7 are frequent. Alkylating agents are carcinogenic in laboratory animals. Although the pathway to leukemogenesis in humans is unknown, a multistep evolution is envisaged. This involves: 1) initiation through induction of errors in DNA, 2) promotion related to stem cell replication following chemotherapy-induced aplasia and 3) propagation related to immunosuppression. It is possible that, as in myeloproliferative disorders, an underlying tendency for leukemia is present in patients with cancer. This may be accentuated by chemotherapy, and more frequently observed due to the longer survival of such patients. The crucial role of chemotherapy in leukemogenesis is evident from data accumulated in non-malignant conditions such as rheumatoid arthritis.
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PMID:Chemotherapy related leukemogenesis. 657 12

The survival, proliferation, differentiation and function of normal hematopoietic cells are negatively and positively controlled by various cytokines. Survival and proliferation of leukemic cells appears to be influenced, at least in vitro, by several cytokines. Among the different hematopoietic cell lineages, megakaryocytopoiesis represents a complex and unique hematopoietic system that is thought to be supported by some well-known cytokines; however, the hypothetical lineage-specific main regulator of platelet production, termed thrombopoietin (TPO) had remained elusive. Recently, characterization of the proto-oncogene c-mpl revealed structural homology with the hematopoietic cytokine receptor superfamily, specific expression on cells of the megakaryocytic lineage and functional involvement in megakaryocytopoiesis. Several groups purified and cloned the MPL ligand. Extensive in vitro and in vivo studies have shown that the MPL ligand has activity in stimulating both megakaryocytopoiesis and platelet production proving that this ligand is the long-sought growth factor TPO itself. The MPL receptor was found at the mRNA and/or protein level in 40-80% of primary acute myeloid leukemia (AML) cases in various series. MPL expression was not limited to certain morphological FAB types, although the highest percentages were seen in the M6 (erythroid) and M7 (megakaryocytic) subclasses. Among the myelodysplastic syndromes (MDS), MPL expression was detected in one third of the cases, in particular in refractory anemia with excess of blasts and chronic myelomonocytic leukemia. Lymphoid malignancies such as acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL) and myeloma were MPL-negative. Among the large panel of human leukemia-lymphoma cell lines studied, MPL expression occurred predominantly in lines with erythro-megakaryocytic phenotypes. Nearly all primary and continuously cultured non-hematopoietic solid tumor samples were negative for MPL expression. A significant portion of AML cases and of erythroid, megakaryocytic and myeloid leukemia cell lines co-expressed TPO and MPL mRNA transcripts, although no biologically active TPO appeared to be secreted by these cells. In several studies TPO induced in vitro proliferation of 14-37% of primary AML cases, predominantly of the M2 and M7 subtypes. TPO significantly enhanced the cytokine-induced growth of AML cells in a substantial fraction of cases responsive to GM-CSF, IL-3, IL-6 or SCF. While none of 30 growth factor-independent erythro-megakaryocytic leukemia cell lines responded to TPO with increased proliferation, TPO strongly augmented the growth of several constitutively cytokine-dependent cell lines (eg HU-3, M-07e, TF-1) which can be made TPO-dependent and used as bioassays. Neither in primary cells nor in cell lines did TPO appear to induce any signs of morphological, functional or immunological differentiation. Expression of the MPL receptor is not correlated with a proliferative response to TPO. In summary, extensive studies on normal human and animal cells demonstrated the specificity and function of the MPL receptor and proved that its ligand TPO is the major physiological regulator of megakaryocytopoiesis. The data reviewed here document the wide expression of the MPL receptor on AML cells and also suggest some proliferative effects on certain leukemia cells, apparently on non-megakaryocytic AML cells as well. Thus, experimental evidence supports the notion that TPO may contribute, at least in part, to leukemogenesis, especially in combination with other hematopoietic cytokines which is of clinical significance. TPO-responsive cell lines represent powerful tools for such analyses.
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PMID:Thrombopoietin: expression of its receptor MPL and proliferative effects on leukemic cells. 875 57

The human thrombin receptor gene has been localized to band q13 of chromosome 5, a site that is at or contiguous to the common proximal breakpoint found in the majority of patients with interstitial deletions involving 5q (5q- syndrome; refractory anemia with dysmegakaryocytopoiesis). Recent evidence suggests that the thrombin receptor may represent the prototype of an emerging family of proteolytically activated receptors that may be clustered within this region of the human genome. The phenotypic heterogeneity evident in patients with the 5q- syndrome may be explained by two (or more) distinct molecular defects-one associated with megakaryocytic dyspoiesis and the other dysregulated myeloid growth potentially related to development of leukemogenesis. Because the thrombin receptor is known to mediate proliferative effects on diverse cells including vascular smooth muscle cells, endothelial cells and megakaryocytes, we have studied the role of this receptor in the pathogenesis of this syndrome using fluorescent in situ hybridization (FISH) analysis. Dual-label FISH using a q12-specific genomic fragment and the TR gene was completed using interphase and metaphase analysis from seven patients with a del(5)(q13q33). These data unequivocally demonstrate that the thrombin receptor gene is located centromeric to the common proximal breakpoint, and is grossly present in the seven patients containing this specific interstitial deletion. Additionally, one patient demonstrated a small proximal rearrangement, most likely representing a paracentric inversion, which has not previously been described within the intact region centromeric to the breakpoint. The biological properties of proteolytically activated receptors are reviewed in more detail, with a focus on the molecular genetics of the thrombin receptor and its potential role in megakaryoctyopoiesis.
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PMID:The human thrombin receptor gene and the 5q-syndrome. 937 91

A cytogenetic and N-ras point mutation study was done in patients with primary myelodysplastic syndrome (MDS) from Rio de Janeiro, Brazil, in order to evaluate the progression of preleukemic states to overt leukemia. Cytogenetic analysis was performed in 50 patients with MDS and clonal chromosomal abnormalities were detected in 19 (38%) of them. Patients with refractory anemia (RA) or with ringed sideroblasts (RARS) presented normal karyotypes or single abnormalities as del(5q) or -Y, while patients in more advanced states as RA with excess of blasts (RAEB), RAEB in transformation (RAEB-t) and chronic myelomonocytic leukemia (CMML) showed complex karyotypes and single abnormalities involving chromosomes 7 or 8, which were related to poor prognosis and elevated risk of transformation to acute myeloid leukemia (AML). The frequency of ras activation was studied in these 50 patients with MDS. Samples of bone marrow were screened for oncogenic point mutations by DNA amplification followed by oligonucleotide hybridization analysis (PCR-ASO) at codon 12 of N-ras proto-oncogene. We detected N-ras point mutations in 21 patients (42%). Progression from MDS to AML was observed in 9 patients (18%). The correlation analysis between N-ras point mutations and specific chromosomal abnormalities indicated that although mutated N-ras was found in cells with del(5q) and monosomy 7, cells with those abnormalities and normal N-ras were also identified. Otherwise trisomy of chromosome 8 showed a correlation with N-ras point mutations and in all cases, patients showed progression of MDS to AML during the follow-up study. MDS comprises a heterogeneous group of hematopoietic disorders and probably several steps are implicated in the evolution to AML. In this work we suggest that one possible pathway of leukemogenesis in MDS includes N-ras point mutations in association with trisomy of chromosome 8.
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PMID:Correlation of N-ras point mutations with specific chromosomal abnormalities in primary myelodysplastic syndrome. 959 69

A 42-year-old female with a mediastinal tumor and massive pleural effusion ws admitted to our hospital in June 1993. Biopsy revealed lymphoblastic lymphoma. She had no evidence of distant metastasis except pleural effusion. Bone marrow examination revealed a normal karyotype (46, XY). The patient had been progression-free for more than 1 year after achieving complete remission by induction, consolidation and maintenance therapy according to the standard chemotherapy and involved-field radiation for lymphoblastic lymphoma. From May 1996 progressive leukopenia and thrombocytopenia developed. The diagnosis of refractory anemia with excess of blasts (RAEB) was made. Subsequently, in November 1996, she developed acute myelogenous leukemia (AML), M4 type by FAB classification. The karyotype of MDS and AML clones involved inversion (3) (q21q26) and monosomy 7. The EVI 1 gene was examined and was proved to be rearranged and activated. This may be the first case among the therapy-related cases of MDS/AML reported whose karyotypes were followed and in which the mRNA expression of EVI 1 gene involved was directly proved in the leukemogenesis process of chemotherapy-induced secondary MDS and AML.
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PMID:Acute myelogenous leukemia with monosomy 7, inv(3) (q21q26), involving activated EVI 1 gene occurring after a complete remission of lymphoblastic lymphoma: a case report. 986 Dec 36

We report five cases of myeloid disorders in which trisomy 21 (+21) was found as the sole acquired karyotypic abnormality, comprising two cases of acute myeloid leukemia (AML) and three cases of myelodysplastic syndrome (MDS). In this series, MDS patients with +21 presented as high grade disease, which included two cases of refractory anemia with excess of blasts (RAEB) and one case of refractory anemia with excess of blasts in transformation (RAEBt), and showed rapid disease progression. Significant thrombocytopenia was observed in all three patients, and bone marrow examination showed a marked reduction in megakaryocytes. AML patients with +21 included one case each of AML-M2 and M4. Despite the poor prognosis reported in AML patients with +21 as the sole abnormality, the patient in our series who was able to complete intensive treatment was cured of disease. The role of +21 in leukemogenesis is reviewed.
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PMID:Trisomy 21 as the sole acquired karyotypic abnormality in acute myeloid leukemia and myelodysplastic syndrome. 1057 14