Mapping chromosomal breakpoints of Burkitt&#39;s t(8;14) translocations far upstream of c-<em>myc</em>.

To analyze the region upstream of c-myc, a number of novel probes were established. These were generated by chromosomal walking starting from the breakpoint of the chromosomal translocation of the B-cell line 380 and by cloning the breakpoint of the translocation of the Burkitt lymphoma cell line IARC/BL72. Using the newly isolated probes a detailed physical map of 500 kilobases of the region upstream of c-myc was established applying pulsed-field gel electrophoresis. The chromosomal breakpoint of IARC/BL72 cells was mapped to a site 55 kilobases 5&prime; of c-myc. A region 20 kilobases in length and containing the breakpoints of 380, EW36, P3HR-1, and Daudi cells was identified 170-190 kilobases upstream of c-myc. In addition the HPV18 integration site in HeLa cells was located between 340 and 500 kilobases 5&prime; of c-myc. The probes were used to define the c-myc amplification units in Colo320-HSR and HL60 cells as well as in four cases of small cell lung cancer. Evidence is provided that the amplicon of HL60 cells is discontinuously organized

Variable breakpoints in Burkitt lymphoma cells with chromosomal t(8;14) translocation separate c-myc and the IgH locus up to several hundred kb.

In about 80% of Burkitt&#39;s lymphoma cases, the tumour cell harbours a reciprocal chromosomal translocation which invariably transposes the coding exons 2 and 3 of c-myc from chromosome 8 to the immunoglobulin heavy chain locus on chromosome 14. Those t(8;14) translocations which disrupt chromosome 8 within or close to the c-myc gene are well documented. In this study we have focussed on t(8;14) translocations with the chromosomal breakpoint far upstream of c-myc. We analyzed the breakpoint position in 44 BL cell lines with t(8;14) translocations of different geographical origin and identified 9 cell lines with the breakpoint more than 14 kb upstream of c-myc. In these cell lines the positions of the translocation junctions on the derivative chromosomes 8q- and 14q+ were mapped by pulsed field gel electrophoresis and multicolour fluorescence in situ hybridization. The breakpoints occur at distances between 55 and more than 340 kb upstream of c-myc with no preferential site on chromosome 8. On chromosome 14, however, the translocation breakpoints are clustered in a narrow region 5&prime; of the intron enhancer of the immunoglobulin heavy chain gene. In 7 of 9 cases, the enhancer is fused to the c-myc bearing sequences of chromosome 8. In two cases, the translocation has occurred in switch &mu; and downstream of C&mu;, respectively. The impact of these results with respect to the hypothesis, that cisregulatory sequences from the immunoglobulin heavy chain locus can deregulate c-myc expression in a manner sufficient for tumour formation, is discussed

Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial

International audienceBACKGROUND: Ponatinib has shown potent activity against chronic myeloid leukaemia that is resistant to available treatment, although it is associated with arterial occlusion. We investigated whether this activity and safety profile would result in superior outcomes compared with imatinib in previously untreated patients with chronic myeloid leukaemia. METHODS: The Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia (EPIC) study was a randomised, open-label, phase 3 trial designed to assess the efficacy and safety of ponatinib, compared with imatinib, in newly diagnosed patients with chronic-phase chronic myeloid leukaemia. Patients from 106 centres in 21 countries were randomly assigned (1:1, with stratification by Sokal score at diagnosis) using an interactive voice and web response system to receive oral ponatinib (45 mg) or imatinib (400 mg) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met. Eligible patients were at least 18 years of age, within 6 months of diagnosis, and Philadelphia chromosome-positive by cytogenetic assessment, with Eastern Cooperative Oncology Group performance status of 0-2, and had not previously been treated with tyrosine kinase inhibitors. The primary endpoint was major molecular response at 12 months. Patients who remained on study and had molecular assessments at specified timepoints were studied at those timepoints. Safety analyses included all treated patients, as per study protocol. This trial is registered with ClinicalTrials.gov, number NCT01650805. FINDINGS: Between Aug 14, 2012, and Oct 9, 2013, 307 patients were randomly assigned to receive ponatinib (n=155) or imatinib (n=152). The trial was terminated early, on Oct 17, 2013, following concerns about vascular adverse events observed in patients given ponatinib in other trials. Trial termination limited assessment of the primary endpoint of major molecular response at 12 months, as only 13 patients in the imatinib group and ten patients in the ponatinib group could be assessed at this timepoint; the proportion of patients achieving a major molecular response at 12 months did not differ significantly between the two groups (eight [80%] of ten patients given ponatinib and five [38%] of 13 patients given imatinib; p=0.074). 11 (7%) of 154 patients given ponatinib and three (2%) of 152 patients given imatinib had arterial occlusive events (p=0.052); arterial occlusive events were designated serious in ten (6%) of 154 patients given ponatinib and in one (1%) of 152 patients given imatinib (p=0.010). The data monitoring committee criterion for risk assessment (significant difference in serious grade 3 or 4 ischaemic events between groups) was not met (five [3%] of 154 vs one [1%] of 152; p=0.21). Grade 3 or 4 adverse events observed in more than 5% of patients in the ponatinib group were increased lipase (22 [14%] of 154 vs three [2%] of 152 with imatinib), thrombocytopenia (19 [12%] of 154 vs ten [7%] of 152 with imatinib), rash (ten [6%] of 154 vs two [1%] of 152 with imatinib). In the imatinib group, grade 3 or 4 adverse events observed in more than 5% of patients were neutropenia (12 [8%] of 152 vs five [3%] of 154 with ponatinib) and thrombocytopenia (ten [7%] of 152 vs 19 [12%] of 154 with ponatinib). Serious adverse events that occurred in three or more patients given ponatinib were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). No serious adverse event occurred in three or more patients given imatinib. INTERPRETATION: The efficacy of ponatinib treatment of newly diagnosed chronic-phase chronic myeloid leukaemia compared with imatinib could not be assessed due to trial termination, but preliminary data suggest there might be benefit, although with more arterial occlusive events than with imatinib at the doses studied. Because the EPIC trial was terminated early, efficacy of ponatinib in this setting remains to be established. FUNDING: ARIAD Pharmaceutical

Ophthalmia nodosa and the oculoglandular syndrome of Parinaud

We present a case of ophthalmia nodosa and Parinaud's oculoglandular syndrome in a patient scratched by a cat six and a half months previously and who gave a positive result to an antigen test for cat scratch disease. In conjunctival swabs were also found urticarial hairs, tracheal fragments, processionary caterpillar oenocytes, and a grain of pollen. The pathogenic part played by each of these foreign bodies is discussed, as well as the possibility of the oculoglandular syndrome being due to the reactivation of a latent virus, the organism of cat scratch disease. So far as we know, this work provides the first description of the association of ophthalmia nodosa with the oculoglandular syndrome of Parinaud