Aneuploidy is a hallmark of human solid cancers that arises from errors in mitosis and results in gain and loss of oncogenes and tumor suppressors. Aneuploidy poses a growth disadvantage for cells grown in vitro, suggesting that cancer cells adapt to this burden. To understand better the consequences of aneuploidy in a rapidly proliferating adult tissue, we engineered a mouse in which chromosome instability was selectively induced in T cells. A flanked by Lox mutation was introduced into the monopolar spindle 1 (Mps1) spindle-assembly checkpoint gene so that Cre-mediated recombination would create a truncated protein (Mps1 DK ) that retained the kinase domain but lacked the kinetochore-binding domain and thereby weakened the checkpoint. In a sensitized p53 +/− background we observed that Mps1 DK/DK mice suffered from rapid-onset acute lymphoblastic lymphoma. The tumors were highly aneuploid and exhibited a metabolic burden similar to that previously characterized in aneuploid yeast and cultured cells. The tumors nonetheless grew rapidly and were lethal within 3-4 mo after birth.

Chromosome instability (CIN) is deleterious to normal cells because of the burden of aneuploidy. However, most human solid tumors have an abnormal karyotype implying that gain and loss of chromosomes by cancer cells confers a selective advantage. CIN can be induced in the mouse by inactivating the spindle assembly checkpoint. This is lethal in the germline but we show here that adult T cells and hepatocytes can survive conditional inactivation of the Mad2l1 SAC gene and resulting CIN. This causes rapid onset of acute lymphoblastic leukemia (T-ALL) and progressive development of hepatocellular carcinoma (HCC), both lethal diseases. The resulting DNA copy number variation and patterns of chromosome loss and gain are tumor-type specific, suggesting differential selective pressures on the two tumor cell types.DOI: http://dx.doi.org/10.7554/eLife.20873.001

Objective: Plexiform neurofibromas (PNs) are complex, benign nerve sheath tumors that occur in approximately 25%-50% of individuals with neurofibromatosis type 1 (NF1). PNs that cause airway compromise or pulmonary dysfunction are uncommon but clinically important. Because improvement in sleep quality or airway function represents direct clinical benefit, measures of sleep and pulmonary function may be more meaningful than tumor size as endpoints in therapeutic clinical trials targeting airway PN.Methods: The Response Evaluation in Neurofibromatosis and Schwannomatosis functional outcomes group reviewed currently available endpoints for sleep and pulmonary outcomes and developed consensus recommendations for response evaluation in NF clinical trials.Results: For patients with airway PNs, polysomnography, impulse oscillometry, and spirometry should be performed to identify abnormal function that will be targeted by the agent under clinical investigation. The functional group endorsed the use of the apnea hypopnea index (AHI) as the primary sleep endpoint, and pulmonary resistance at 10 Hz (R 10 ) or forced expiratory volume in 1 or 0.75 seconds (FEV 1 or FEV 0.75 ) as primary pulmonary endpoints. The group defined minimum changes in AHI, R 10 , and FEV 1 or FEV 0.75 for response criteria. Secondary sleep outcomes include desaturation and hypercapnia during sleep and arousal index. Secondary pulmonary outcomes include pulmonary resistance and reactance measurements at 5, 10, and 20 Hz; forced vital capacity; peak expiratory flow; and forced expiratory flows.Conclusions: These recommended sleep and pulmonary evaluations are intended to provide researchers with a standardized set of clinically meaningful endpoints for response evaluation in trials of NF1-related airway PNs. Plexiform neurofibromas (PNs) are complex, benign nerve sheath tumors that occur in approximately 25%-50% of individuals with neurofibromatosis type 1 (NF1). The frequency and type of PN-associated morbidities are influenced by tumor location and volume (figure).1-7 A total of 15%-38% of all PNs occur in the head/neck region and 6%-25% occur in the thorax/mediastinum. Airway PNs are a subset of PNs that arise in close proximity to the airway. Symptomatic PNs that cause airway compromise or pulmonary dysfunction are uncommon (reported in 5%-7% of children with PNs) but clinically important. If left untreated, these lesions can be fatal. Surgical resection is often not feasible, and tracheostomy is required in some patients. 3,5 Obstructive sleep apnea (OSA) is caused by repeated collapse of the airway during sleep resulting in partial obstruction (hypopnea) or total obstruction (apnea). In the general pediatric