Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia

Despite extensive insights into the underlying genetics and biology of acute myeloid leukemia (AML), overall survival remains poor and new therapies are needed. We found that casein kinase 1 α (Csnk1a1), a serine-threonine kinase, is essential for AML cell survival in vivo. Normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected by shRNA-mediated knockdown of Csnk1a1. To identify downstream mediators of Csnk1a1 critical for leukemia cells, we performed an in vivo pooled shRNA screen and gene expression profiling. We found that Csnk1a1 knockdown results in decreased Rps6 phosphorylation, increased p53 activity, and myeloid differentiation. Consistent with these observations, p53-null leukemias were insensitive to Csnk1a1 knockdown. We further evaluated whether D4476, a casein kinase 1 inhibitor, would exhibit selective antileukemic effects. Treatment of leukemia stem cells (LSCs) with D4476 showed highly selective killing of LSCs over normal HSPCs. In summary, these findings demonstrate that Csnk1a1 inhibition causes reduced Rps6 phosphorylation and activation of p53, resulting in selective elimination of leukemia cells, revealing Csnk1a1 as a potential therapeutic target for the treatment of AML

Noise and Robustness in Phyllotaxis

A striking feature of vascular plants is the regular arrangement of lateral organs on the stem, known as phyllotaxis. The most common phyllotactic patterns can be described using spirals, numbers from the Fibonacci sequence and the golden angle. This rich mathematical structure, along with the experimental reproduction of phyllotactic spirals in physical systems, has led to a view of phyllotaxis focusing on regularity. However all organisms are affected by natural stochastic variability, raising questions about the effect of this variability on phyllotaxis and the achievement of such regular patterns. Here we address these questions theoretically using a dynamical system of interacting sources of inhibitory field. Previous work has shown that phyllotaxis can emerge deterministically from the self-organization of such sources and that inhibition is primarily mediated by the depletion of the plant hormone auxin through polarized transport. We incorporated stochasticity in the model and found three main classes of defects in spiral phyllotaxis – the reversal of the handedness of spirals, the concomitant initiation of organs and the occurrence of distichous angles – and we investigated whether a secondary inhibitory field filters out defects. Our results are consistent with available experimental data and yield a prediction of the main source of stochasticity during organogenesis. Our model can be related to cellular parameters and thus provides a framework for the analysis of phyllotactic mutants at both cellular and tissular levels. We propose that secondary fields associated with organogenesis, such as other biochemical signals or mechanical forces, are important for the robustness of phyllotaxis. More generally, our work sheds light on how a target pattern can be achieved within a noisy background

In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling

We used an in vivo small hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo and for human leukemia cells in xenotransplantation studies. In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation via the intracellular kinase Syk. In contrast, loss of Itgb3 in normal hematopoietic stem and progenitor cells did not affect engraftment, reconstitution, or differentiation. Finally, using an Itgb3 knockout mouse model, we confirmed that Itgb3 is dispensable for normal hematopoiesis but is required for leukemogenesis. Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML.National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant P01 CA108631)National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant RC1 CA145229)National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant R01 CA140292)National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant CA148180

Pollination ecology and reproductive success in Jack-in-the Pulpit (Arisaema triphyllum) in Quebec (Canada)

International audienc

Pollination ecology and reproductive success in Jack-in-the pulpit (Arisaema triphyllum) in Québec (Canada)

Pollination ecology and reproductive success of Jack-in-the-pulpit (Arisaema triphyllum) were studied in two natural populations in Québec, Canada. Individual A. triphyllum plants can be of three types: male, female or bisexual. In both populations studied, the presence of bisexual inflorescences was not negligible (13%), where 'female' and 'male' bisexual plants were categorised according to the relative number of stamens and ovaries. 'Male bisexual' plants produce only pollen and 'female bisexual' plants produce only fruit. Hence, A. triphyllum is a true dioecious plant, as each plant only reproduces through either the male or the female function. 'Female bisexual' plants were equivalent to female plants in terms of visitation rate by insects, fructification rate and production of berries and seeds. Neither agamospermy in female plants nor self-pollination in 'female bisexual' plants was found, thus A. triphyllum relies on insects for cross-pollination. Despite the long flowering cycle, a low visitation rate was documented: only 20-40% of inflorescences were visited, according to gender, by a mean of 1.5 insects. In this study, Mycetophilidae represented the most generically diversified and abundant family, as well as the most efficient insect pollinator, especially the genera Docosia and Mycetophila

Pollination ecology and reproductive success in Jack-in-the Pulpit (Arisaema triphyllum) in Quebec (Canada)

International audienc