Tumour suppressor genes encode a broad class of molecules whose mutational attenuation contributes to malignant progression. In the canonical situation, the tumour suppressor is completely inactivated through a two-hit process involving a point mutation in one allele and chromosomal deletion of the other1. Here, to identify tumour suppressor genes in lymphoma, we screen a short hairpin RNA library targeting genes deleted in human lymphomas. We functionally identify those genes whose suppression promotes tumorigenesis in a mouse lymphoma model. Of the nine tumour suppressors we identified, eight correspond to genes occurring in three physically linked ‘clusters’, suggesting that the common occurrence of large chromosomal deletions in human tumours reflects selective pressure to attenuate multiple genes. Among the new tumour suppressors are adenosylmethionine decarboxylase 1 (AMD1) and eukaryotic translation initiation factor 5A (eIF5A), two genes associated with hypusine, a unique amino acid produced as a product of polyamine metabolism through a highly conserved pathway2. Through a secondary screen surveying the impact of all polyamine enzymes on tumorigenesis, we establish the polyamine–hypusine axis as a new tumour suppressor network regulating apoptosis. Unexpectedly, heterozygous deletions encompassing AMD1 and eIF5A often occur together in human lymphomas and co-suppression of both genes promotes lymphomagenesis in mice. Thus, some tumour suppressor functions can be disabled through a two-step process targeting different genes acting in the same pathway.

IntroductionTreatment strategies for patients with acute myeloid leukemia (AML) are based on various prognostic factors, including age and performance status of the patient, as well as cytogenetic and molecular characteristics of the leukemic clone. Key objectives in predicting the prognosis of AML are to define patients with high risk of relapse to apply more intensive therapy such as allogeneic stem cell transplantation, and also to withhold aggressive therapy when final success seems highly unlikely. 1 Hematologic malignancies are developed and maintained not only by the molecular events inside the malignant cell clone, but also by their interaction with the microenvironment. The cross-talk between stroma and malignant cells has a major impact on pathophysiological behavior and progress of the disease. [2][3][4] Osteopontin (OPN) is a secreted glycoprotein of the SIBLING family that is involved in physiologic and pathophysiologic processes. 5 The different effects of OPN are due to its multiple receptors and isoforms. Cleavage of OPN leads to a molecular mass that facilitates binding to various receptors such as CD44, ␣9␤1, and ␣4␤7. 5 In vitro, OPN has been shown to influence adhesion and migration of smooth muscle cells, endothelial cells, and melanoma cells. 5 OPN exerts dual functions as a chemoattractant cytokine and as an extracellular component. 5 Previous studies indicated a role for OPN in several malignancies. Whereas most previous studies focused on solid cancers, 6,7 there have been recent advances in deciphering the role of OPN in hematologic malignancies. [8][9][10] For example, it has been shown that OPN contributes to BM adhesion and migration of hematopoietic stem cells (HSCs). 11 OPN may act as a negative regulator of HSCs through the inhibition of HSC division. 11 HSC adhesion to osteoblasts leads to a resting state of these cells in the stem cell niche, with protection from cytotoxic and apoptotic stimuli. 12 In the present study, we analyzed the expression of OPN in BM, AML blasts, and serum of AML patients. Our results show that the expression of OPN is increased at the mRNA and protein levels in AML patients compared with healthy controls. We also show that OPN is an independent prognostic marker in AML. Methods Patient characteristicsIHC analysis cohort. BM sections from 84 patients with newly diagnosed, untreated AML were chosen randomly. Three control samples were taken from patients with various diseases but normal BM morphology. BM core biopsies were obtained at presentation. After core biopsy, BM aspiration was obtained through a separate puncture for cytological analysis. All patients were treated uniformly according to the German AML Cooperative The online version of this article contains a data supplement.Data reported herein were presented in part at the annual meeting of the German Society for Hematology and Oncology; October 4, 2010; Berlin, Germany.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact...

BackgroundFalciparum Malaria, an infectious disease caused by the apicomplexan parasite Plasmodium falciparum, is among the leading causes of death and morbidity attributable to infectious diseases worldwide. In Gabon, Central Africa, one out of four inpatients have severe malarial anemia (SMA), a life-threatening complication if left untreated. Emerging drug resistant parasites might aggravate the situation. This case control study investigates biomarkers of enhanced hemolysis in hospitalized children with either SMA or mild malaria (MM).Methods and FindingsNinety-one children were included, thereof 39 SMA patients. Strict inclusion criteria were chosen to exclude other causes of anemia. At diagnosis, erythrophagocytosis (a direct marker for extravascular hemolysis, EVH) was enhanced in SMA compared to MM patients (5.0 arbitrary units (AU) (interquartile range (IR): 2.2–9.6) vs. 2.1 AU (IR: 1.3–3.9), p<0.01). Furthermore, indirect markers for EVH, (i.e. serum neopterin levels, spleen size enlargement and monocyte pigment) were significantly increased in SMA patients. Markers for erythrocyte ageing, such as CD35 (complement receptor 1), CD55 (decay acceleration factor) and phosphatidylserine exposure (annexin-V-binding) were investigated by flow cytometry. In SMA patients, levels of CD35 and CD55 on the red blood cell surface were decreased and erythrocyte removal markers were increased when compared to MM or reconvalescent patients. Additionally, intravascular hemolysis (IVH) was quantified using several indirect markers (LDH, α-HBDH, haptoglobin and hemopexin), which all showed elevated IVH in SMA. The presence of both IVH and EVH predicted the need for blood transfusion during antimalarial treatment (odds ratio 61.5, 95% confidence interval (CI): 8.9–427). Interestingly, this subpopulation is characterized by a significantly lowered reticulocyte production index (RPI, p<0.05).ConclusionsOur results show the multifactorial pathophysiology of SMA, whereby EVH and IVH play a particularly important role. We propose a model where removal of infected and non-infected erythrocytes of all ages (including reticulocytes) by EVH and IVH is a main mechanism of SMA. Further studies are underway to investigate the mechanism and extent of reticulocyte removal to identify possible interventions to reduce the risk of SMA development.