Constructive role of dissipation for driven coupled bosonic modes

We describe four cases of childhood B-cell progenitor acute lymphoblastic leukaemia (BCP-ALL) and one of T-cell (T-ALL) with unexpected numbers of interphase signals for ETV6 with an ETV6-RUNX1 fusion probe. Three fusion negative cases each had a telomeric part of 12p terminating within intron 2 of ETV6, attached to sequences from 5q, 7p and 7q, respectively. Two fusion positive cases, with partial insertions of ETV6 into chromosome 21, also had a breakpoint in intron 2. Fluorescence in situ hybridisation ( FISH), array comparative genomic hybridization (aCGH) and Molecular Copy-Number Counting (MCC) results were concordant for the T-cell case. Sequences downstream of TLX3 on chromosome 5 were deleted, leaving the intact gene closely apposed to the first two exons of ETV6 and its upstream promoter. qRT-PCR showed a significant upregulation of TLX3. In this study we provide the first incontrovertible evidence that the upstream promoter of ETV6 attached to the first two exons of the gene was responsible for the ectopic expression of a proto-oncogene that became abnormally close as the result of deletion and translocation. We have also shown breakpoints in intron 2 of ETV6 in two cases of insertion with ETV6-RUNX1 fusion

A single centre experience of mastocytosis: Guy's and St Thomas' NHS Foundation Trust

Although both MRD and karyotype are powerful determinants of outcome in childhood ALL, few studies have examined the kinetics of MRD clearance by cytogenetics. In ALL2003, patients are stratified by NCI criteria to a three or four drug induction. MRD is assessed at day 29 and week 11 using a standardised and quality controlled RQPCR of 21patient specific immunoglobulin or T-cell receptor rearrangements. MRD risk groups were defined as: (1) High risk MRD410-4 at day 29 (HR); (2) Low risk MRD negative or o10-4 at day 29 and negative at week 11 (LR); or (3) MRD indeterminate risk. Among 1000 patients entered into the trial, 98% were eligible for these analyses, 94% had a successful cytogenetics and 57% were assigned to a clinically relevant MRD groups. Among these latter 555 patients, 54% were MRD-HR whereas 45% were MRD-LR. Collectively, patients with high-risk cytogenetics ‘t(9;22), o40 chromosomes, 11q23/MLL, t(17;19) and iAMP21’ were more likely to be MRDHR ‘83% vs 52%, P50.003’. Patients with ETV6-RUNX1 fusion were less likely to be MRD-HR ‘28% vs 63%, Po0.001’ whereas high hyperdiploid patients were more likely ‘64% vs 49%, P50.002’. However, excluding ETV6-RUNX1 patients from the latter analysis revealed that high hyperdiploid patients were as likely to be MRDHR as other ETV6-RUNX1 negative patients. T-ALL patients were also more likely to be MRD-HR compared to BCP-ALL patients ‘70% vs 52%, P50.022’. In particular, 9/10 patients with t(5;14)/TLX3- BCL11B fusion and 6/6 patients with SIL-TAL1 fusion were MRD-HR. In conclusion, we have clearly demonstrated that MRD status varies by cytogenetic subgroup with ETV6-RUNX1 patients having the fastest MRD clearance rate. Despite the good prognosis associated with high hyperdiploidy, these patients were as likely to be MRD-HR as other standard risk patients. Longer follow-up is required to determine the clinical significance of this finding

The Clinical Impact and Molecular Biology of del(17p) in Multiple Myeloma Treated with Conventional or Thalidomide-Based Therapy

Hemizygous deletion of 17p (del(17p)) has been identified as a variable associated with poor prognosis in myeloma, although its impact in the context of thalidomide therapy is not well described. The clinical outcome of 85 myeloma patients with del(17p) treated in a clinical trial incorporating both conventional and thalidomide-based induction therapies was examined. The clinical impact of deletion, low expression, and mutation of TP53 was also determined. Patients with del(17p) did not have inferior response rates compared to patients without del(17p), but, despite this, del(17p) was associated with impaired overall survival (OS) (median OS 26.6 vs. 48.5 months, P < 0.001). Within the del(17p) group, thalidomide induction therapy was associated with improved response rates compared to conventional therapy, but there was no impact on OS. Thalidomide maintenance was associated with impaired OS, although our analysis suggests that this effect may have been due to confounding variables. A minimally deleted region on 17p13.1 involving 17 genes was identified, of which only TP53 and SAT2 were underexpressed. TP53 was mutated in < 1% in patients without del(17p) and in 27% of patients with del(17p). The higher TP53 mutation rate in samples with del(17p) suggests a role for TP53 in these clinical outcomes. In conclusion, del(17p) defined a patient group associated with short survival in myeloma, and although thalidomide induction therapy was associated with improved response rates, it did not impact OS, suggesting that alternative therapeutic strategies are required for this group. (C) 2011 Wiley-Liss, Inc