Laszlo et al. Page 3187

Exploratory gene expression array analyses by Laszlo and colleagues suggested that multimerin-1 (MMRN1) could be a novel predictive biomarker in acute myeloid leukemia (AML). To follow up on these findings, MMRN1 expression was studied in two recent Children's Oncology Group trials. Although associated with some adverse disease-risk features, high MMRN1 expression was independently associated with shorter overall- and event-free survival as well as a higher relapse risk. These data identify MMRN1 expression as a novel biomarker that may refine AML risk-stratification.

Miyake et al. Page 3286

Selective inhibitors of nuclear export system (NES) have been developed for cancer therapy, but the underlying mechanisms were not well understood. To clarify the mechanisms, Miyake and colleagues performed proteomic analyses and identified a previously unrecognized mechanism whereby inhibition of NES causes eukaryotic initiation factor 5A (eIF5A) accumulation in mitochondria and induces apoptosis; this effect is regulated by direct binding with insulin-like growth factor 2 mRNA binding protein (IGF2BP1). These data provide a new understanding of eIF5A regulation in response to inhibition of NES and provide a potent anticancer therapeutic strategy.

Di Stefano et al. Page 3307

FGFR-TACC gene fusions have emerged as frequent chromosomal translocations across different tumors. To explore their role as therapeutic targets, Di Stefano and colleagues designed a screen covering all FGFR-TACC variants. FGFR-TACC fusions cluster in IDH-wild type grade II-IV glioma, co-occur with CDK4/MDM2 amplification, are alternative to EGFR alterations, and are uniformly expressed in the positive tumors. Preclinical experiments with FGFR-TACC-positive glioma treated with a specific FGFR inhibitor show strong antitumor effects and treatment of two patients with recurrent glioblastoma result in clinical improvement and tumor shrinkage. These results validate the selection of FGFR inhibitors for the treatment of FGFR-TACC-positive cancer.

Lambertz et al. Page 3327

Neuroblastoma is an often lethal embryonal tumor arising from sympathetic neuronal precursor cells. ALK mutations occur in 10% of all tumors, and clinical trials with ALK inhibitors are underway. Because tumors often become resistant to small molecule inhibitors, Lambertz and colleagues decided to unravel the signaling components downstream of ALK to identify additional targets for combination therapy. The authors identified RET regulated through the ALK-AKT-FOXO3a pathway and propose RET inhibition as a possible novel combination therapy. Furthermore, mutant ALK also installs a negative MAPK feedback loop that may have consequences for resistance to novel targeted treatments.