Individuals with neurofibromatosis type 1 (NF1) are predisposed to certain cancers including juvenile chronic myelogenous leukaemia (JCML). The NF1 tumour-suppressor gene encodes a protein (neurofibromin) that accelerates GTP hydrolysis on Ras proteins. Here we show that primary leukaemic cells from children with NF1 show a selective decrease in NF1-like GTPase activating protein (GAP) activity for Ras but retain normal cellular GAP activity. Leukaemic cells also show an elevated percentage of Ras in the GTP-bound conformation. JCML cells are hypersensitive to granulocyte-macrophage colony stimulating factor (GM-CSF), and we observed a similar pattern of aberrant growth in haematopoietic cells from Nf1-/- mouse embryos. These data define a specific role for neurofibromin in negatively regulating GM-CSF signaling through Ras in haematopoietic cells and they suggest that hypersensitivity to GM-CSF may be a primary event in the development of JCML.
The most accurate assessment of the site of occlusion, infarct core, salvageable brain tissue, and collateral circulation in patients suspected of acute stroke is afforded by a combination of PCT and CTA.
Background-Previous studies have suggested that baseline computed tomographic (CT) scans might be a useful tool for selecting particular ischemic stroke patients who would benefit from thrombolysis. The aim of the present study was to assess whether the baseline CT scan, assessed with the Alberta Stroke Program Early CT Score (ASPECTS), could identify ischemic stroke patients who might particularly benefit from intra-arterial thrombolysis of middle cerebral artery occlusion. Methods-Baseline and 24-hour follow-up CT scans of patients randomized within 6 hours of symptoms to intra-arterial thrombolysis with recombinant pro-urokinase or control in the PROACT-II study were retrospectively scored by using ASPECTS. Patients were stratified into those with ASPECTS Ͼ7 or Յ7. Independent functional outcome at 90 days was compared between the 2 strata according to treatment assignment. Results-The analysis included 154 patients with angiographically confirmed middle cerebral artery occlusion. The unadjusted risk ratio of an independent functional outcome, in favor of treatment, in the ASPECTS Ͼ7 group was 5.0 (95% confidence interval [CI], 1.3 to 19.2) compared with 1.0 (95% CI, 0.6 to 1.9) in the ASPECTS Յ7 group. After adjustment for baseline characteristics, the risk ratio in the ASPECTS score Ͼ7 was 3.2 (95% CI, 1.2 to 9.1). Similar favorable treatment effects were observed when secondary outcomes were used, but these did not reach statistical significance. Conclusions-Ischemic stroke patients with a baseline ASPECTS Ͼ7 were 3 times more likely to have an independent functional outcome with thrombolytic treatment compared with control. Patients with a baseline ASPECTS Յ7 were less likely to benefit from treatment. This observation suggests that ASPECTS can be both a useful clinical tool and an important method of baseline risk stratification in future clinical trials of acute stroke therapy.
A novel alteration in exon 1 of KRAS was detected by single strand conformational polymorphism analysis of DNA amplified from the bone marrow of a 4-year-old child with myeloid leukemia. Sequencing of this mutant allele revealed an insertion of three nucleotides between codons 10 and 11 resulting in an in-frame insertion of glycine. Expression of the mutant protein in NIH 3T3 cells caused cellular transformation, and expression in COS cells activated the Ras-mitogen-activated protein kinase signaling pathway. Surprisingly, Ras⅐GTP levels measured in COS cells established that this novel mutant accumulates to 90% in the GTP state, considerably higher than a residue 12 mutant. Biochemical analysis confirmed that the higher Ras⅐GTP levels correspond to a dramatic decrease in intrinsic GTP hydrolysis as well as resistance to GTPase-activating proteins. This mutation is the first dominant Ras mutation found in human cancer that does not involve residues 12, 13, or 61, and its biochemical properties should help elucidate the mechanism of oncogenic activation.
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