Highlights d A selective, orally bioavailable Menin-MLL inhibitor, VTP50469, is developed d Displacement of Menin from chromatin leads to loss of MLL from specific loci d Treatment with VTP50469 leads to suppression of a subset of MLL fusion target genes d Treatment with VTP50469 improves survival in PDX models of MLL-r ALL

Many insects feed on only one or a few types of host. These host specialists often evolve a preference for chemical cues emanating from their host and develop mechanisms for circumventing their host's defenses. Adaptations like these are central to evolutionary biology, yet our understanding of their genetics remains incomplete. Drosophila sechellia, an emerging model for the genetics of host specialization, is an island endemic that has adapted to chemical toxins present in the fruit of its host plant, Morinda citrifolia. Its sibling species, D. simulans, and many other Drosophila species do not tolerate these toxins and avoid the fruit. Earlier work found a region with a strong effect on tolerance to the major toxin, octanoic acid, on chromosome arm 3R. Using a novel assay, we narrowed this region to a small span near the centromere containing 18 genes, including three odorant binding proteins. It has been hypothesized that the evolution of host specialization is facilitated by genetic linkage between alleles contributing to host preference and alleles contributing to host usage, such as tolerance to secondary compounds. We tested this hypothesis by measuring the effect of this tolerance locus on host preference behavior. Our data were inconsistent with the linkage hypothesis, as flies bearing this tolerance region showed no increase in preference for media containing M. citrifolia toxins, which D. sechellia prefers. Thus, in contrast to some models for host preference, preference and tolerance are not tightly linked at this locus nor is increased tolerance per se sufficient to change preference. Our data are consistent with the previously proposed model that the evolution of D. sechellia as a M. citrifolia specialist occurred through a stepwise loss of aversion and gain of tolerance to M. citrifolia's toxins. HALF of all insects interact with plants (Grimaldi and Engel 2005). Most phytophageous insects, however, use only a few plant genera for food, mating, and oviposition (Bernays and Chapman 1994). Changes in host use can result in both new species and new adaptations (Ehrlich and Raven 1964;Janz 2011). For example, the evolution of a new host specialization may have contributed to the formation of new species in pea aphids (Acyrthosiphon) among others (Via 2001;Matsubayashi et al. 2010). Adapting to a new host can drive genetic and phenotypic change that is critical for isolating nascent species. In some cases, specialization has a price: Increased performance on the new host correlates with reduced performance on other hosts (Futuyma and Moreno 1988;Jaenike 1990;Fry et al. 1996;Scheirs et al. 2005; Via and Hawthorne 2005). This scenario poses a new challenge for the nascent specialist, as it must keep together alleles for finding and selecting the appropriate host ("preference") along with those for utilizing that host ("performance," e.g., physiologically adapting to that host's secondary compounds or nutritional content; Jaenike 1990; Janz 2011). Theory suggests that a genetic correlation betwe...

Purpose: Patients with relapsed pediatric solid malignancies have few therapeutic options, and many of these patients die of their disease. B7-H3 is an immune checkpoint protein encoded by the CD276 gene that is overexpressed in many pediatric cancers. Here, we investigate the activity of the B7-H3–targeting antibody–drug conjugate (ADC) m276-SL-PBD in pediatric solid malignancy patient-derived (PDX) and cell line–derived xenograft (CDX) models. Experimental Design: B7-H3 expression was quantified by RNA sequencing and by IHC on pediatric PDX microarrays. We tested the safety and efficacy of m276-SL-PBD in two stages. Randomized trials of m276-SL-PBD of 0.5 mg/kg on days 1, 8, and 15 compared with vehicle were performed in PDX or CDX models of Ewing sarcoma (N = 3), rhabdomyosarcoma (N = 4), Wilms tumors (N = 2), osteosarcoma (N = 5), and neuroblastoma (N = 12). We then performed a single mouse trial in 47 PDX or CDX models using a single 0.5 m/kg dose of m276-SL-PBD. Results: The vast majority of PDX and CDX samples studied showed intense membranous B7-H3 expression (median H-score 177, SD 52). In the randomized trials, m276-SL-PBD showed a 92.3% response rate, with 61.5% of models showing a maintained complete response (MCR). These data were confirmed in the single mouse trial with an overall response rate of 91.5% and MCR rate of 64.4%. Treatment-related mortality rate was 5.5% with late weight loss observed in a subset of models dosed once a week for 3 weeks. Conclusions: m276-SL-PBD has significant antitumor activity across a broad panel of pediatric solid tumor PDX models.

A metamorphosis from rosette to inflorescence in many annuals shifts photosynthetic tissue from a two-dimensional array in the soil boundary layer during cool months to a three-dimensional structure in the troposphere as spring progresses. We propose that this shift allows escape from both self-shading and an increasingly stressful boundary layer microclimate, permitting continued increases in growth. As a first step in exploring this hypothesis, we compared the lifetime C gain, water loss, and instantaneous water use efficiency (WUE) of five Arabidopsis thaliana genotypes by measuring gas exchange across the life cycle. On average, the inflorescence contributed 55% (± 5% SE) of lifetime C gain, but only 25% of lifetime water loss. Mean inflorescence WUE was nearly fourfold that of the rosette. The inflorescence continued to fix C after rosette senescence. The percentage inflorescence: total C gain varied among genotypes, from 36% to 93%. Genotypes differed in WUE for both structures. We suggest that local climates may have selected for divergence in these traits. For many annuals and winter annuals, understanding C and water budgets and their evolution must include measures of both rosette and inflorescence gas exchange.

In this article, Matute et al. report an experiment in which they generated eight interspecific admixed populations using two species pairs of Drosophila. They found that in both species pairs, and across all experimental replicates... The consequences of hybridization are varied, ranging from the origin of new lineages, introgression of some genes between species, to the extinction of one of the hybridizing species. We generated replicate admixed populations between two pairs of sister species of Drosophila: D. simulans and D. mauritiana; and D. yakuba and D. santomea. Each pair consisted of a continental species and an island endemic. The admixed populations were maintained by random mating in discrete generations for over 20 generations. We assessed morphological, behavioral, and fitness-related traits from each replicate population periodically, and sequenced genomic DNA from the populations at generation 20. For both pairs of species, species-specific traits and their genomes regressed to those of the continental species. A few alleles from the island species persisted, but they tended to be proportionally rare among all sites in the genome and were rarely fixed within the populations. This paucity of alleles from the island species was particularly pronounced on the X-chromosome. These results indicate that nearly all foreign genes were quickly eliminated after hybridization and that selection against the minor species genome might be similar across experimental replicates.