Serotonin as an integrator of leech behavior and muscle mechanical performance.

The obliquely striated muscle in the leech body wall has a broad functional repertoire; it provides power for both locomotion and suction feeding. It also operates over an unusually high strain range, undergoing up to threefold changes in length. Serotonin (5-HT) may support this functional flexibility, integrating behavior and biomechanics. It can act centrally, promoting motor outputs that drive body wall movements, and peripherally, modulating the mechanical properties of body wall muscle. During isometric contractions 5-HT enhances active force production and reduces resting muscle tone. We therefore hypothesized that 5-HT would increase net work output during the cyclical contractions associated with locomotion and feeding. Longitudinal strains measured during swimming, crawling and feeding were applied to body wall muscle in vitro with the timing and duration of stimulation selected to maximize net work output. The net work output during all simulated behaviors significantly increased in the presence of 100µM 5-HT relative to the 5-HT-free control condition. Without 5-HT the muscle strips could not achieve a net positive work output during simulated swimming. The decrease in passive tension associated with 5-HT may also be important in reducing muscle antagonist work during longitudinal muscle lengthening. The behavioral and mechanical effects of 5-HT during locomotion are clearly complementary, promoting particular behaviors and enhancing muscle performance during those behaviors. Although 5-HT can enhance muscle mechanical performance during simulated feeding, low in vivo activity in serotonergic neurons during feeding may mean that its mechanical role during this behavior is less important than during locomotion.

MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L.

The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia (MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-associated gene expression corresponded with dependence of MLL-AF9 leukemia on Dot1l in vivo. These data point to DOT1L as a potential therapeutic target in MLL-rearranged leukemia.