Biosonar navigation above water I: estimating flight height.

Locomotion and foraging on the wing require precise navigation in more than just the horizontal plane. Navigation in three dimensions and, specifically, precise adjustment of flight height are essential for flying animals. Echolocating bats drink from water surfaces in flight, which requires an exceptionally precise vertical navigation. Here, we exploit this behavior in the bat, Phyllostomus discolor, to understand the biophysical and neural mechanisms that allow for sonar-guided navigation in the vertical plane. In a set of behavioral experiments, we show that for echolocating bats, adjustment of flight height depends on the tragus in their outer ears. Specifically, the tragus imposes elevation-specific spectral interference patterns on the echoes of the bats' sonar emissions. Head-related transfer functions of our bats show that these interference patterns are most conspicuous in the frequency range ∼55 kHz. This conspicuousness is faithfully preserved in the frequency tuning and spatial receptive fields of cortical single and multiunits recorded from anesthetized animals. In addition, we recorded vertical spatiotemporal response maps that describe neural tuning in elevation over time. One class of units that were very sharply tuned to frequencies ∼55 kHz showed unusual spatiotemporal response characteristics with a preference for paired echoes where especially the first echo originates from very low elevations. These behavioral and neural data provide the first insight into biosonar-based processing and perception of acoustic elevation cues that are essential for bats to navigate in three-dimensional space.

Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML.

Chemotherapy resistance is the main impediment in the treatment of acute myeloid leukaemia (AML). Despite rapid advances, the various mechanisms inducing resistance development remain to be defined in detail. Here we report that loss-of-function mutations (LOF) in the histone methyltransferase EZH2 have the potential to confer resistance against the chemotherapeutic agent cytarabine. We identify seven distinct EZH2 mutations leading to loss of H3K27 trimethylation via multiple mechanisms. Analysis of matched diagnosis and relapse samples reveal a heterogenous regulation of EZH2 and a loss of EZH2 in 50% of patients. We confirm that loss of EZH2 induces resistance against cytarabine in the cell lines HEK293T and K562 as well as in a patient-derived xenograft model. Proteomics and transcriptomics analysis reveal that resistance is conferred by upregulation of multiple direct and indirect EZH2 target genes that are involved in apoptosis evasion, augmentation of proliferation and alteration of transmembrane transporter function. Our data indicate that loss of EZH2 results in upregulation of its target genes, providing the cell with a selective growth advantage, which mediates chemotherapy resistance.

Loss of KDM6A confers drug resistance in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm resulting from the malignant transformation of myeloid progenitors. Despite intensive chemotherapy leading to initial treatment responses, relapse caused by intrinsic or acquired drug resistance represents a major challenge. Here, we report that histone 3 lysine 27 demethylase KDM6A (UTX) is targeted by inactivating mutations and mutation-independent regulation in relapsed AML. Analyses of matched diagnosis and relapse specimens from individuals with KDM6A mutations showed an outgrowth of the KDM6A mutated tumor population at relapse. KDM6A expression is heterogeneously regulated and relapse-specific loss of KDM6A was observed in 45.7% of CN-AML patients. KDM6A-null myeloid leukemia cells were more resistant to treatment with the chemotherapeutic agents cytarabine (AraC) and daunorubicin. Inducible re-expression of KDM6A in KDM6A-null cell lines suppressed proliferation and sensitized cells again to AraC treatment. RNA expression analysis and functional studies revealed that resistance to AraC was conferred by downregulation of the nucleoside membrane transporter ENT1 (SLC29A1) by reduced H3K27 acetylation at the ENT1 locus. Our results show that loss of KDM6A provides cells with a selective advantage during chemotherapy, which ultimately leads to the observed outgrowth of clones with KDM6A mutations or reduced KDM6A expression at relapse.