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)

More than thirty small guanine nucleotide-binding proteins related to the ras-encoded oncoprotein, termed Ras or p21ras, are known. They regulate many fundamental processes in all eukaryotic cells, such as growth, vesicle traffic and cytoskeletal organization. GTPase-activating proteins (GAPs) accelerate the intrinsic rate of GTP hydrolysis of Ras-related proteins, leading to down-regulation of the active GTP-bound form. For p21ras, two GAP proteins are known, rasGAP and the neurofibromatosis (NF1) gene product. There is evidence that rasGAP may also be a target protein for regulation by Ras and be involved in downstream signalling. We have purified a GAP protein for p21rho, which is involved in the regulation of the actin cytoskeleton. Partial sequencing of rhoGAP reveals significant homology with the product of the bcr (breakpoint cluster region) gene, the translocation breakpoint in Philadelphia chromosome-positive chronic myeloid leukaemias. We show here that the carboxy-terminal domains of the bcr-encoded protein (Bcr) and of a Bcr-related protein, n-chimaerin, are both GAP proteins for the Ras-related GTP-binding protein, p21rac. This result suggest that Bcr could be a target for regulation by Rac and has important new implications for the role of bcr translocations in leukaemia.
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PMID:Bcr encodes a GTPase-activating protein for p21rac. 190 16

The genetic determinant responsible for virulence in Moloney murine leukemia virus (MoMuLV) induced T-cell lymphomagenesis has recently been mapped [J Virol 63:471-480, 1989] by homologous genomic fragment exchange between MoMuLV and MoMuLV-TB to the Clal/Xbal at the 3' end of the genome. This region of MoMuLV and MoMuLV-TB differs in 11 nucleotides. Of these 11 nucleotide differences, 9 are distributed within the two CORE, the two distal NF1, and the two GRE/LVa elements of the enhancer. Since both the CORE binding sites of MoMuLV-TB are mutated with respect to those of MoMuLV, we compared nuclear proteins of a thymus-bone marrow cell line and a T-lymphoma cell line (EMT), which bind to the wild-type and mutant CORE binding sites. Using both the bandshift assay and southwestern analysis with labeled synthetic deoxyoligonucleotides, we showed that a 42-kDa protein from TB and EMT cells bound specifically to the MoMuLV CORE element. The T----C transversion of nucleotide 6 of the CORE consensus, TGTGGT/CTAA, significantly reduced binding of the 42-kDa TB and EMT cell factors. However, the transversion of nucleotide 3 from T----C had little effect on the binding of the 42-kDa protein to the CORE element. In addition, the 42-kDa protein bound weakly to the CCAAT element of MoMuLV. A recombinant virus, NwtTB-6, was generated by introducing the two CORE mutations of MoMuLV-TB into the MoMuLV genome. Although the latency period of NwtTB-6 in the induction of lymphoma was not significantly different from that of MoMuLV, preliminary findings suggest that the lymphoma induced by NwtTB-6 may be more widely distributed.
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PMID:A single mutation in one of the CORE elements of Moloney murine leukemia virus reduced binding of a 42-kDa T lymphoma cell nuclear factor but did not affect lymphomagenesis. 234 87

Chimeric constructs were generated by exchanging genomic fragments between the potent T-cell lymphoma inducer Moloney murine leukemia virus (MoMuLV) and its derivative MoMuLV-TB, which induces T-cell lymphoma after a relatively longer latent period. Analysis of the T-cell lymphoma-inducing potential of the hybrid viruses that were obtained localized the primary determinant critical to efficient T-cell lymphoma induction to the MoMuLV ClaI-XbaI fragment which comprises 48 nucleotides (nt) of p15E, p2E, the 3'-noncoding sequence, and 298 nt of U3. The 438-base-pair ClaI-XbaI fragments of MoMuLV and MoMuLV-TB differed in only 11 nt. Nine mutations were found within the enhancer. These mutations occurred within the two CORE, the two GRE-LVa, and two of the four NF1 nuclear factor-binding motifs. MoMuLV-TB replicated better than MoMuLV in thymus-bone marrow (TB) cells, a cultured cell line of lymphoid origin. In addition, MoMuLV-TB and NwtTB-2, a recombinant virus with the ClaI-SmaI fragment of MoMuLV-TB in a MoMuLV background, replicated in thymocytes as efficiently as did MoMuLV or TBNwt-2, the reciprocal recombinant virus, with the ClaI-SmaI fragment of MoMuLV in a MoMuLV-TB background. Like NwtTB-4, a recombinant virus with the ClaI-XbaI fragment of MoMuLV-TB in a MoMuLV background, NwtTB-2 induced lymphoma after a long latent period. The finding given above suggests that thymotropism is not the only factor that determines the T-cell lymphoma-inducing potential of MoMuLV. It appears likely that mutations in one or more of the MoMuLV-TB nuclear factor-binding motifs may have altered the interaction of the enhancer with specific nuclear factors; this, in turn, may affect the T-cell lymphoma-inducing potential of MoMuLV-TB.
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PMID:The reduced virulence of the thymotropic Moloney murine leukemia virus derivative MoMuLV-TB is mapped to 11 mutations within the U3 region of the long terminal repeat. 278 65

The frequency of RAS activation was studied in 48 patients with acute myeloid leukaemia (AML) or with myelodysplastic syndromes (MDS), in order to address the question of whether patients possessing monosomy 7 or other alterations of chromosome 7 have a higher incidence of RAS activation than those lacking chromosome 7 abnormalities. Samples were screened for oncogenic point mutation by DNA amplification followed by oligonucleotide hybridization analysis at codons 12, 13 and 61 of N-RAS and codons 12 and 13 of K-RAS. Two additional samples were considered to have activated RAS due to additional karyotypic abnormalities t(5;12) or loss of both copies of chromosome 17 and hence, the neurofibromatosis (NF1) loci. The group of chronic myelomonocytic leukaemia (CMML) patients had activated RAS in 4/11 cases and inclusion of two CMMLt patients (with monosomy 7) brings this incidence to 5/13. No change in frequency of RAS activation was seen between groups containing de novo AML samples with or without chromosome 7 abnormalities (1/5 and 2/12, respectively). However, assessment of MDS samples in the process of, or subsequent to, leukaemic progression showed a difference between the two groups. The frequency of RAS activation in samples with monosomy 7 was 4/9 samples while none of the seven samples without chromosome 7 changes showed RAS activation. The co-existence of RAS activation and monosomy 7 in MDS indicates that these lesions can co-operate in the multistep process of leukemogenesis.
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PMID:Possible co-existence of RAS activation and monosomy 7 in the leukaemic transformation of myelodysplastic syndromes. 750 Jun 52

We have previously described a patient with chronic myelomonocytic leukemia who exhibited a mutation (del-10:-8) in the splice-acceptor region in front of the FLR exon of the NF1 tumor suppressor gene. In order to evaluate whether this mutation indeed affects correct splicing of this exon we used an exon trap approach. Our data unequivocally prove the functional relevance of this NF1 mutation. Exon trapping thus represents an attractive strategy to study the consequences of putative splice-site mutations if RNA samples are not available.
Leukemia 1995 May
PMID:Exon trap analysis of a NF1 splice-site mutation in a chronic myelomonocytic leukemia patient. 776 57

Human neurofibromatosis type 1 is a dominant disease caused by the inheritance of a mutant allele of the NF1 gene. In order to study NF1 function, we have constructed a mouse strain carrying a germline mutation in the murine homologue. Heterozygous animals do not exhibit the classical symptoms of the human disease, but are highly predisposed to the formation of various tumour types, notably phaeochomocytoma, a tumour of the neural crest-derived adrenal medulla, and myeloid leukaemia, both of which occur with increased frequency in human NF1 patients. The wild-type Nf1 allele is lost in approximately half of the tumours from heterozygous animals. In addition, homozygosity for the Nf1 mutation leads to abnormal cardiac development and mid-gestational embryonic lethality.
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PMID:Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. 792 Jun 53

There is a well-known raised risk of leukaemia in children with neurofibromatosis type 1 (NF-1). We carried out the first detailed population-based study of leukaemia and non-Hodgkin lymphoma (NHL) associated with NF-1 in order to estimate the risk and elucidate the relationship between these conditions. Over the 17 year study period there were five cases of chronic myelomonocytic leukaemia (CMML) in patients with NF-1 (relative risk 221; 95% CI 71-514), 12 cases of acute lymphoblastic leukaemia (ALL) (relative risk 5.4; 95% CI 2.8-9.4) and five cases of NHL (relative risk 10.0; 95% CI 3.3-23.4). Marrow cytogenetics could be reviewed for seven patients. Specific abnormalities found were monosomy 21 in a child with CMML and 7p+, 17p- in a child with ALL. No abnormalities were reported of 17q, which includes the NF1 gene. CMML occurred predominantly in boys, who also had a family history of NF-1. ALL and NHL were more often found in children with no previous family history.
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PMID:Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. 869 73

We investigated mutations in the GTPase activating protein-related domain of the neurofibromatosis type 1 gene (NF1-GRD) and its expression in each phase of chronic myelogenous leukemia (CML). Samples from 45 cases in chronic phase (CP), 41 in acute phase, and four CML cell lines were examined for mutations in the NF1-GRD by single-strand conformation polymorphism (SSCP) analysis and allele specific restriction analysis (ASRA). No mutations were detected in the exon where frequent mutations have recently been reported in human tumors, namely the FLR exon. We also examined for point mutations of the N-ras gene but found no mutations either. In 23 samples from CML cases and four CML cell lines, expression of two types of the NF1-GRD transcripts, type I and type II, were examined by NF1-GRD-specific polymerase chain reaction-based densitometric analysis and by the quantitative assay with coamplification of the NF1-GRD and beta-actin transcripts. Consequently, although expression level of type I transcripts varied among the samples, type II expression was increased in CML cell lines and a minor increase in type II expression was observed in the samples in acute phase compared with CP. However, this difference in type II expression between CP and acute phase was so small that changes of NF1-GRD transcripts as well as NF1-GRD or N-ras mutations might not be responsible for the progression of CML.
Leukemia 1994 Jun
PMID:Analysis of mutations and expression of GAP-related domain of the neurofibromatosis type 1 (NF1) gene in the progression of chronic myelogenous leukemia. 820 76

We performed longitudinal analyses of chromosomes and studied the configuration of NRAS, TP53, NF1, and cFMS genes in 70 patients with myelodysplastic syndrome(MDS). The NRAS mutations were detected in 6 patients(9%) at codons 12 or 13. The TP53 mutations were found in 10 patients(14%) in exons 4 through 8. Longitudinal studies revealed that the NRAS mutation was a late-appearing event, while the TP53 mutations were detectable at the presentation of MDS. No patients had both NRAS and TP53 mutations, simultaneously. NF1 and cFMS genes showed any mutational event among these 70 patients. Patients with a TP53 mutation had a significantly shorter survival time than those with an NRAS mutation or those without NRAS or TP53 mutation. However, patients who showed an NRAS mutation had a shorter survival time once the mutation emerged, similar to that of patients with a TP53 mutation.
Leukemia 1997 Apr
PMID:Genetic aberrations in the development and subsequent progression of myelodysplastic syndrome. 920 48

Cytochrome P450 CYP2D6 polymorphism is an autosomal recessive trait leading to impaired sparteine/ debrisoquine metabolism in 5-10% of the Caucasian population. Previous studies have associated affected individuals (poor metabolizers = PM) with susceptibility to bladder cancer and various forms of leukemia. In many other cancer forms, the data remain contradictory. A PCR assay allows the convenient screening of about 90% of known mutations resulting in the PM phenotype. Since in patients with neurofibromatosis type 2, we had observed a significantly increased rate of CYP2D6 mutations leading to PM and apparently predisposing for NF2, we extended our investigation to tumor and peripheral blood samples obtained from NF1 patients. Although the number of cases investigated remains low, the study indicated that during tumor formation no changes occurred at the mutational hot spot within the CYP2D6 sequence. Moreover, no loss of heterozygosity was notable. However, the frequency of the mutated allele in the NF1 individuals is comparable to that of neurofibromatosis type 2 and above that observed in breast and colon cancer, or meningiomas.
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PMID:Debrisoquine hydroxylase gene polymorphism in neurofibromatosis type 1. 949 60


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