RUNX1 mutations in acute myeloid leukemia are associated with distinct clinico-pathologic and genetic features.

We evaluated the frequency, genetic architecture, clinico-pathologic features and prognostic impact of RUNX1 mutations in 2439 adult patients with newly-diagnosed acute myeloid leukemia (AML). RUNX1 mutations were found in 245 of 2439 (10%) patients; were almost mutually exclusive of AML with recurrent genetic abnormalities; and they co-occurred with a complex pattern of gene mutations, frequently involving mutations in epigenetic modifiers (ASXL1, IDH2, KMT2A, EZH2), components of the spliceosome complex (SRSF2, SF3B1) and STAG2, PHF6, BCOR. RUNX1 mutations were associated with older age (16-59 years: 8.5%; ⩾60 years: 15.1%), male gender, more immature morphology and secondary AML evolving from myelodysplastic syndrome. In univariable analyses, RUNX1 mutations were associated with inferior event-free (EFS, P<0.0001), relapse-free (RFS, P=0.0007) and overall survival (OS, P<0.0001) in all patients, remaining significant when age was considered. In multivariable analysis, RUNX1 mutations predicted for inferior EFS (P=0.01). The effect of co-mutation varied by partner gene, where patients with the secondary genotypes RUNX1mut/ASXL1mut (OS, P=0.004), RUNX1mut/SRSF2mut (OS, P=0.007) and RUNX1mut/PHF6mut (OS, P=0.03) did significantly worse, whereas patients with the genotype RUNX1mut/IDH2mut (OS, P=0.04) had a better outcome. In conclusion, RUNX1-mutated AML is associated with a complex mutation cluster and is correlated with distinct clinico-pathologic features and inferior prognosis.

Metamorphosis enhances the effects of metal exposure on the mayfly, Centroptilum triangulifer.

The response of larval aquatic insects to stressors such as metals is used to assess the ecological condition of streams worldwide. However, nearly all larval insects metamorphose from aquatic larvae to winged adults, and recent surveys indicate that adults may be a more sensitive indicator of stream metal toxicity than larvae. One hypothesis to explain this pattern is that insects exposed to elevated metal in their larval stages have a reduced ability to successfully complete metamorphosis. To test this hypothesis we exposed late-instar larvae of the mayfly, Centroptilum triangulifer, to an aqueous Zn gradient (32-476 µg/L) in the laboratory. After 6 days of exposure, when metamorphosis began, larval survival was unaffected by zinc. However, Zn reduced wingpad development at concentrations above 139 µg/L. In contrast, emergence of subimagos and imagos tended to decline with any increase in Zn. At Zn concentrations below 105 µg/L (hardness-adjusted aquatic life criterion), survival between the wingpad and subimago stages declined 5-fold across the Zn gradient. These results support the hypothesis that metamorphosis may be a survival bottleneck, particularly in contaminated streams. Thus, death during metamorphosis may be a key mechanism explaining how stream metal contamination can impact terrestrial communities by reducing aquatic insect emergence.