Transcriptional network control of normal and leukaemic haematopoiesis.

Transcription factors (TFs) play a key role in determining the gene expression profiles of stem/progenitor cells, and defining their potential to differentiate into mature cell lineages. TF interactions within gene-regulatory networks are vital to these processes, and dysregulation of these networks by TF overexpression, deletion or abnormal gene fusions have been shown to cause malignancy. While investigation of these processes remains a challenge, advances in genome-wide technologies and growing interactions between laboratory and computational science are starting to produce increasingly accurate network models. The haematopoietic system provides an attractive experimental system to elucidate gene regulatory mechanisms, and allows experimental investigation of both normal and dysregulated networks. In this review we examine the principles of TF-controlled gene regulatory networks and the key experimental techniques used to investigate them. We look in detail at examples of how these approaches can be used to dissect out the regulatory mechanisms controlling normal haematopoiesis, as well as the dysregulated networks associated with haematological malignancies.

Adenoviremia has limited clinical impact in the majority of patients following alemtuzumab-based allogeneic stem cell transplantation in adults.

BACKGROUND: Adenovirus infection is a potentially serious complication of allogeneic hematopoietic stem cell transplantation (HSCT) and has been reported to occur more frequently following T-cell-depleted reduced-intensity HSCT. However, the true incidence and clinical significance as well as the relationship of disease to viremic titer remain unclear due to wide variation in study populations and methodology. METHODS: We performed weekly surveillance blood testing by quantitative polymerase chain reaction on all adult recipients of alemtuzumab-based reduced-intensity HSCT at our institution between January 2008 and January 2011. We collated this with clinical data on treatment and outcomes of adenovirus infection. RESULTS: Of 116 HSCT patients analyzed, 14 (12.1%) had adenoviremia with a titer >200 copies/mL. Median time to first detectable titer was 28 days post-HSCT (range, 10-347), and median time to maximum titer was 49 days (range, 16-368). Underlying disease diagnosis (lymphoid > myeloid) and recipient cytomegalovirus (CMV) serostatus (positive > negative) were significantly correlated with adenoviremia. Only 5 patients (with high peak titers of 99 000-2 500 000 copies/mL) received cidofovir; 1 died from complications relating to adenovirus and concurrent CMV infection. CONCLUSIONS: We detected adenoviremia at quantifiable levels in only 12.1% of HSCT patients. Attributable mortality was low (0.9% of the entire cohort, 7% of those with adenoviremia) because even infections associated with high viral titers responded to reduction in immunosuppression and treatment with cidofovir in the majority. The clinical significance of adenoviral infection in patients receiving alemtuzumab-based HSCT appears to be less than that previously reported, and only rarely does infection lead to significant morbidity and mortality.

Outcomes in older adults with acute lymphoblastic leukaemia (ALL): results from the international MRC UKALL XII/ECOG2993 trial.

Although the incidence rate of acute lymphoblastic leukaemia (ALL) is slightly higher in older than in younger adults, response rates to induction chemotherapy and survival rates are poorer. The contribution of disease-related versus treatment-related factors remains unclear. We analysed 100 older patients (aged 55-65 years) treated on the UKALLXII/ECOG2993 trial compared with 1814 younger patients (aged 14-54 years). Baseline characteristics, induction chemotherapy course, infections, drug reductions and survival outcomes were compared. There were more Philadelphia-positive (Ph+) patients in the older group (28% vs. 17%, P = 0·02), and a trend towards higher combined cytogenetic risk score (46% vs. 35%, P = 0·07). The complete remission rate in older patients was worse (73% vs. 93%, P < 0·0001) as was 5-year overall survival (21% vs. 41%, P < 0·0001) and event-free survival (EFS) (19% vs. 37%, P < 0·0001). Older patients had more infections during induction (81% vs. 70%, P = 0·05), and drug reductions (46% vs. 28%, P = 0·0009). Among older patients, Ph+ and cytogenetic risk category as well as infection during induction predicted for worse EFS. Poorer outcomes in these patients are partly due to cytogenetic risk, but there is significant morbidity and mortality during induction chemotherapy with frequent delays and drug reductions. New approaches, including better risk stratification and use of targeted therapies, could improve treatment for these patients.