Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-ras oncogenes activated by point mutation have been frequently detected in various types of human leukemias. Analysis of a large number of leukemias revealed that activated N-ras oncogenes were observed preferentially in AML, AMoL, T-ALL and Null-ALL but rarely in CML and B-cell leukemia. These results suggest that N-ras oncogene plays an important role in human leukemogenesis. Activated N-ras oncogenes were also detected in myelodysplastic syndrome (MDS) that is considered to be a preleukemic disease. MDS patients bearing an activated N-ras oncogene frequently showed leukemic progression of the disease, suggesting that an activated N-ras oncogene can be a critical factor for prognosis of MDS patients. Thus, detection of an activated N-ras oncogene is useful for diagnosis, prognostic evaluation and therapeutic decision. Recently, we demonstrated that detection of the minimal residual disease by analysis of N-ras oncogene can lead to improvement of the remission rate in leukemias. Moreover, we made it possible to screen N-ras oncogene by a sensitive non-radioactive method. Our research procedure seems to be a good model for clinical application of the molecular biological technique.
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PMID:[Activation of ras oncogene in myelodysplastic syndrome and acute myelogenous leukemia]. 205 67

Polymerase chain reaction (PCR) was applied to detect the structural change accompanying the activation of oncogenes in hematological malignancies and preleukemic states. Point mutation of N-ras oncogene was examined by oligonucleotide differential hybridization coupled with PCR. Five out of 17 AML patients were shown to have mutated N-ras gene. These mutations could be used as a genetic marker to diagnose the residual malignant cells. Philadelphia chromosome in CML was examined by cDNA synthesis and PCR with successful results. PCR was shown to be a highly versatile and sensitive method which would be invaluable in clinical diagnosis.
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PMID:Application of polymerase chain reaction to detect activated oncogenes in hematological malignancies. 262 64

Point mutations of the N-ras oncogene are relatively common in acute myelogenous leukemia (AML) cells, occurring in some 25% to 50% of patient samples. We used a technique involving the direct nucleotide sequencing of in vitro amplified N-ras genomic fragments to determine the frequency of N-ras point mutations in chronic myeloid leukemia (CML) cells at various stages of the disease. This approach will detect N-ras point mutations in a mixed population of cells if the mutation is present in 25% or more of the cells. We could not demonstrate any point mutation at N-ras codons 12,13 or 59-63 in any of the 44 CML cases analyzed, which included 21 blast crisis samples. In contrast with AML N-ras point mutations are exceedingly rare in CML.
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PMID:Rare occurrence of N-ras point mutations in Philadelphia chromosome positive chronic myeloid leukemia. 264 46

Results of our study on the activation of N-ras oncogene by point mutation in human leukemia and myelodysplastic syndrome have been described in this article. Point mutation was observed mainly on the 12th, 13th and 61st amino acid codon of ras genes. Therefore, oligomers containing mutations at these codons were used as probes for dot blot analysis of DNA derived from patient's bone marrow cells or leukemia cells. Polymerase chain reaction technique was used to amplify the DNA of ras genes containing 12th, 13th and 61st codons. By this technique, sensitivity of the method to detect the point mutations in ras oncogene was remarkably increased. Detection of the mutation in ras gene is considered to be very useful for the diagnosis, determination of remission and finding of relapse at an early stage. Study on the fused gene of bcr-abl, its mRNA and protein in chronic myelogenous leukemia is a good and reliable method to prove the existence of Ph1 positive chromosome by gene technology. Identification of the Ph1 acute lymphoblastic leukemia (ALL) has become possible by studying abl oncogene in Ph1 positive ALL. This method can be used also for the diagnosis of Ph1 ALL.
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PMID:[Oncogenes in human leukemia]. 265 Jun 33

Minute alterations of the p53 tumor suppressor gene and N-ras oncogene were investigated in 106 samples for the p53 gene and 23 samples for the N-ras gene obtained from patients with various types of hematologic malignancies using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and direct nucleotide sequencing. Mobility shifts suggesting sequence alteration were observed in 9 cases (8.5%) in exons 5 through 8 containing evolutionarily highly conserved regions of the p53 gene by PCR-SSCP; missense point mutations in 3 cases (1 acute myelogenous leukemia (AML), 1 chronic myelogenous leukemia (CML) in the accelerated phase, and 1 CML in the blast crisis), silent point mutation in 1 case (malignant lymphoma), and frame shift mutations due to insertions and deletions causing stop codons in 3 cases (1 AML, 1 CML in the chronic phase and 1 acute lymphoblastic leukemia (ALL)). p53 gene alterations did not always cluster within evolutionarily highly conserved regions, and there were various base change forms in cases with p53 point mutations. p53 mutations were detected in 2 cases out of 4 cases with 17 monosomy. There was no case with p53 gene alteration in myelodysplastic syndrome (MDS) cases. Mobility shifts suggesting sequence alteration were observed in 5 cases (22%) in exon 1 and 2 of the N-ras gene by PCR-SSCP. 3 cases (1 MDS, 1 MDS overt AML and 1 ALL) were detected to contain missense point mutations. However, simultaneous mutations in both the genes were detected in only 2 cases out of 23, thereby indicating infrequent occurrence of concomitant mutation of both the genes in hematologic malignancies. Alterations of the p53 and the N-ras genes are involved in the tumorigenesis, progression and prognosis of at least some cases of hematologic malignancies, in spite that they are relatively infrequent.
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PMID:[Molecular study on minute alterations of the p53 and the N-ras genes in hematologic malignancies]. 792 79

Mutations within N-ras oncogene codons 12, 13, and 61 occur in approximately 25-30% of patients with acute nonlymphocytic leukemia and at a lower frequency (6-20%) in patients with acute lymphocytic leukemia. Moreover, N-ras mutations have been described in patients with chronic myeloid leukemia (CML) in blast crisis but have not been observed during the chronic phase of the disease. In view of the morphological and clinical similarities between acute leukemia and the blast crisis of CML, the question was raised whether the presence of N-ras mutations is associated with the phenotype of acute leukemia. We investigated leukemic cells from 100 patients with CML for the presence of N-ras mutations in the mutational hot spot codons. The cases analyzed included 87 diagnosed with different types of blast crisis and 13 cases in accelerated or chronic phase of the disease. Fragments from N-ras exons I and II containing the codons of interest were amplified by polymerase chain reaction and analyzed for the presence of point mutations by three different technical approaches, including specific oligonucleotide hybridization, direct sequencing, and single-strand conformation polymorphism analysis. N-ras mutations were not detected in any of the CML patients investigated. Only one patient, in whom the initial diagnosis of CML-blast crisis had been revised to chronic myelomonocytic leukemia, displayed an N-ras mutation within codon 13. Our data strongly suggest that N-ras mutations do not play a role in myeloid or lymphoid blast crisis of CML.
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PMID:Absence of N-ras mutations in myeloid and lymphoid blast crisis of chronic myeloid leukemia. 803 17

Molecular events associated with the transformation into blast crisis phase in Ph1-positive CML were analyzed in the present study. The 9;22 chromosomal translocation in CML generates the bcr/abl fused gene coding P210bcr/abl that has enhanced tyrosine kinase activity. In 55 CML cases, Southern and RT-PCR analysis revealed that breakpoints of the bcr gene on chromosome 22q11 were clustered in M-bcr, except for one case and no obvious difference was observed between chronic and crisis phases. However, blast crisis cells displayed enhanced the expression of bcr/abl mRNA, when compared with those in chronic phase cells. By DNA transfection and PCR analysis, the point-mutational activation of N-ras oncogene was rarely identified, and no point-mutational activation of fms gene was found in the crisis phase cases. On the other hand, 2 out of 13 crisis cases contained gross alteration of p53 anti-oncogene. Furthermore, all 4 myeloid crisis cases and K562 cells showed disappearance of the P53 transcript, and MC3 cells derived from a myeloid crisis case showed an aberrant transcript, whereas chronic phase cases, Ph1-positive ALL cell lines and lymphoid crisis cases including NALM-1 cells showed normal expression of the P53 gene. At present, the precise mechanism associated with the blastic trans-formation in CML remain to be determined. The present study suggested one possibility that a selective and progressive process of Ph1 clone with high expression of the bcr/abl gene may be involved with the transformation into non-lymphoid crisis phases from chronic phases. In addition, this progression may be accelerated by the alteration of p53 anti-oncogene, or/and rarely by the point-mutational activation of ras oncogene family.
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PMID:[Molecular analysis of transformation into blast crisis in chronic myelogenous leukemia]. 850 66

Mutations that activate the N-ras oncogene are among the most frequently detected genetic alterations in human acute myeloid leukemias (AMLs), Philadelphia chromosome-negative myeloproliferative disorders (MPDs), and myelodysplastic syndromes (MDSs). However, because N-ras has not been shown to induce these disorders in an in vivo model, the role of N-ras in the evolution of myeloid leukemia is unclear. To investigate the potential of N-ras to induce myeloid leukemia, lethally irradiated mice were reconstituted with bone marrow (BM) cells infected with a retroviral vector carrying activated N-ras. Approximately 60% of these mice developed hematopoietic disorders, including severe MPDs resembling human chronic myelogenous leukemia (CML) or AML with differentiation (French-American-British [FAB] classification M2). Other reconstituted mice succumbed to hematopoietic defects that were pathologically similar to human MDSs. The latter disorders appeared to be due to a myeloid impairment that was demonstrated by enumeration of day-12 colony-forming units-spleen (CFU-S) and by in vitro colony assays. A high level of apoptosis associated with thymic atrophy and peripheral blood (PB) lymphopenia was also evident in N-ras reconstituted mice. Our results are consistent with a model in which antiproliferative effects are a primary consequence of N-ras mutations and secondary transforming events are necessary for the development of myeloid leukemia. This is the first report of an in vivo model for N-ras induced MPD and leukemia.
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PMID:Mutant N-ras induces myeloproliferative disorders and apoptosis in bone marrow repopulated mice. 1006 78