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

The morphology of CLL revisited: the clinical significance of prolymphocytes and correlations with prognostic/molecular markers in the LRF CLL4 trial

Historically, an increase in the percentage and number of circulating prolymphocytes in chronic lymphocytic leukaemia (CLL) has been associated with strong expression of surface immunoglobulin, trisomy 12 and a poor outcome. This study re-examines the biological and clinical significance of increased peripheral blood prolymphocytes in 508 patients at entry into the randomized UK Leukaemia Research Fund CLL4 trial. It also investigates the associations between increased prolymphocytes and a comprehensive array of biomarkers. 270 patients (53%) had <5% prolymphocytes, 167 (33%) had 5-9%, 60 (12%) had 10-14% and 11 (2%) had ?15% prolymphocytes. We show that a higher proportion of prolymphocytes (?10%) was independently associated with NOTCH1 mutations (P = 0·006), absence of 13q deletion (P = 0·001), high CD38 expression (P = 0·02) and unmutated IGHV genes (P = 0·01). Deaths due to Richter syndrome were significantly more common amongst patients who had ?10% vs <10% prolymphocytes (13% vs 2%) respectively (P < 0·0001). ?10% prolymphocytes was also associated with a shorter progression-free survival (Hazard ratio [HR] 1·50 [95% confidence interval [CI]: 1·16-1·93], P = 0·002) and overall survival (HR 1·99 [95% CI: 1·53-2·59], P < 0·0001). Our data support the routine examination of blood films in CLL and suggest that a finding of an increased proportion of prolymphocytes may be a trigger for further evaluation of clinical and laboratory features of progressive disease

Chromatin accessibility maps of chronic lymphocytic leukemia identify subtypespecific epigenome signatures and associated transcription regulatory networks

Chronic lymphocytic leukemia (CLL) is characterized by substantial clinical heterogeneity, despite relatively few genetic alterations. To provide a basis for studying epigenome deregulation in CLL, we established genome-wide chromatin accessibility maps for 88 CLL samples from 55 patients using the ATAC-seq assay. These data were further complemented by ChIPmentation and RNA-seq profiling in ten samples. Based on this dataset, we devised and applied a bioinformatic method that links chromatin profiles to clinical annotations. Our analysis identified sample-specific variation on top of a shared core of CLL regulatory regions. IGHV mutation status – which distinguishes the two major subtypes of CLL – was accurately predicted by the chromatin profiles, and gene regulatory networks inferred for IGHV-mutated vs. IGHV-unmutated samples identified characteristic regulatory differences between these two disease subtypes. In summary, we found widespread heterogeneity in the CLL chromatin landscape, established a community resource for studying epigenome deregulation in leukemia, and demonstrated the feasibility of chromatin accessibility mapping in cancer cohorts and clinical research

The morphology of CLL revisited: the clinical significance of prolymphocytes and correlations with prognostic/molecular markers in the LRF CLL4 trial.

Historically, an increase in the percentage and number of circulating prolymphocytes in chronic lymphocytic leukaemia (CLL) has been associated with strong expression of surface immunoglobulin, trisomy 12 and a poor outcome. This study re-examines the biological and clinical significance of increased peripheral blood prolymphocytes in 508 patients at entry into the randomized UK Leukaemia Research Fund CLL4 trial. It also investigates the associations between increased prolymphocytes and a comprehensive array of biomarkers. 270 patients (53%) had <5% prolymphocytes, 167 (33%) had 5-9%, 60 (12%) had 10-14% and 11 (2%) had ≥15% prolymphocytes. We show that a higher proportion of prolymphocytes (≥10%) was independently associated with NOTCH1 mutations (P = 0·006), absence of 13q deletion (P = 0·001), high CD38 expression (P = 0·02) and unmutated IGHV genes (P = 0·01). Deaths due to Richter syndrome were significantly more common amongst patients who had ≥10% vs <10% prolymphocytes (13% vs 2%) respectively (P < 0·0001). ≥10% prolymphocytes was also associated with a shorter progression-free survival (Hazard ratio [HR] 1·50 [95% confidence interval [CI]: 1·16-1·93], P = 0·002) and overall survival (HR 1·99 [95% CI: 1·53-2·59], P < 0·0001). Our data support the routine examination of blood films in CLL and suggest that a finding of an increased proportion of prolymphocytes may be a trigger for further evaluation of clinical and laboratory features of progressive disease

An analysis of observed daily maximum wind gusts in the UK

The greatest attention to the UK wind climatology has focused upon mean windspeeds, despite a knowledge of gust speeds being essential to a variety of users. This paper goes some way to redressing this imbalance by analysing observed daily maximum gust speeds from a 43-station network over the period 1980–2005. Complementing these data are dynamically downscaled reanalysis data, generated using the PRECIS Regional Climate Modelling system, for the period 1959–2001. Inter-annual variations in both the observed and downscaled reanalysis gust speeds are presented, with a statistically significant (at the 95% confidence interval) 5% increase across the network in daily maximum gust speeds between 1959 and the early 1990s, followed by an apparent decrease. The benefit of incorporating dynamically downscaled reanalysis data is revealed by the fact that the decrease in gust speeds since 1993 may be placed in the context of a very slight increase displayed over the longer 1959–2001 period. Furthermore, the severity of individual windstorm events is considered, with high profile recent events placed into the context of the long term record. A daily cycle is identified from the station observations in the timing of the daily maximum gust speeds, with an afternoon peak occurring between 12:00–15:00, exhibiting spatial and intra-annual variations

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukemia cells through downregulation of Mcl-1

The pro-survival Bcl-2 family member Mcl-1 is expressed in chronic lymphocytic leukemia (CLL), with high expression correlated with progressive disease. The spliceosome inhibitor spliceostatin A (SSA), is known to regulate Mcl-1 and so here we assessed the ability of SSA to elicit apoptosis in CLL. SSA induced apoptosis of CLL cells at low nanomolar concentrations in a dose- and time-dependent manner, but independently of SF3B1 mutational status, IGHV status and CD38 or ZAP70 expression. However, normal B and T cells were less sensitive than CLL cells (P=0.006 and P&lt;0.001, respectively). SSA altered the splicing of anti-apoptotic MCL-1L to MCL-1s in CLL cells coincident with induction of apoptosis. Overexpression studies in Ramos cells suggested Mcl-1 was important for SSA-induced killing since its expression inversely correlated with apoptosis (P=0.001). IL4 and CD40L, present in patient lymph nodes, are known to protect tumor cells from apoptosis and significantly inhibited SSA, ABT-263 and ABT-199 induced killing following administration to CLL cells (P=0.008). However, by combining SSA with the Bcl-2/Bcl-xL antagonists ABT-263 or ABT-199, we were able to overcome this pro-survival effect. We conclude that SSA combined with Bcl-2/Bcl-xL antagonists may have therapeutic utility for CL

The outcome of Chronic lymphocytic leukaemia patients with 97% IGHV gene identity to germline is distinct from cases with <97% identity and similar to those with 98% identity.

IGHV gene mutational status has prognostic significance in chronic lymphocytic leukaemia (CLL) but the percentage of mutations that correlates best with clinical outcome remains controversial. We initially studied 558 patients from diagnosis and found significant differences in median time to first treatment (TTFT) among Stage A patients and in overall survival (OS) for the whole cohort, between cases with <97% and 97-98·99% identity and between cases with 97-98·99% and ≥99% identity, when cases from the IGHV3-21 Stereotype Subset #2 were excluded. A significant difference in progression-free survival (PFS) and OS between those with <97% and 97-98·99% identity, but not between those with 97-98·99% and ≥99% identity was also observed in a validation cohort comprising 460 patients in the UK CLL4 trial. Cox Regression analyses in the Stage A cohort revealed that a model which incorporated <97%, 97-98·99% and ≥99% identity as subgroups, was a better predictor of TTFT in CLL than using the 98% cut-off. Multivariate analysis selected the three mutational subgroups as independent predictors of TTFT in Stage A patients, and of OS in the diagnostic cohort. This study highlights that cases with 97% identity should not be considered to have the same prognosis as other cases with mutated IGHV genes defined as <98% identity to germline

Telomere length predicts progression and overall survival in chronic lymphocytic leukemia: data from the UK LRF CLL4 trial

Telomere erosion and fusion play an important role in the pathology of many common human malignancies including CLL.1,2 Previous studies in CLL have shown that short telomeres defined on the basis of the median value or receiver operating characteristic (ROC) analysis are associated with unmutated IGHV genes, poor risk genomic abnormalities, genomic complexity and high expression of CD38, CD49d, and ZAP70 whereas long telomeres are associated with increasing IGHV mutational load, isolated deletion of 13q and low CD49d expression. In addition, in predominantly diagnostic or mixed patient cohorts, telomere length (TL) predicts time to first treatment and/or overall survival (OS) in multivariate analyses of models incorporating established biomarkers. 3-7 However uncertainties about the most clinically relevant measure of telomere length, the optimal choice of assay, the need for assay standardisation and the lack of published data on the prognostic value of TL in patients entered into randomised trials have hindered the implementation of TL measurement into routine clinical practice. We have attempted to address these issues by measuring telomere length using monochrome multiplex Q-PCR (MMQ-PCR) in 384 patients at randomisation into the UK LRF CLL4 phase 3 chemotherapy trial (Table S1), of whom 111 samples were also screened by single telomer