O'Donnell, C. | bioRxiv Science

bioRxiv2017

MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia

HIGHLIGHTSO_LIMEF2C S222 phosphorylation is a specific marker of chemotherapy resistance in diagnostic AML patient specimens.\nC_LIO_LIMEF2C S222 phosphorylation is dispensable for normal hematopoiesis in mice, as established using genome editing in vivo, but is required for MLL-AF9 induced leukemogenesis.\nC_LIO_LIMARK kinases specifically phosphorylate MEF2C S222, potentiating its transcriptional activity.\nC_LIO_LIChemical inhibition of MARK-induced MEF2C phosphorylation overcomes chemotherapy resistance of and exhibits selectivity toxicity against MEF2C-activated human AML cells.\nC_LI\n\nSUMMARYIn acute myeloid leukemia, chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that Mef2cS222A/S222A knock-in mutant mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MLL-AF9. MEF2C phosphorylation was required for leukemia stem cell maintenance, and induced by MARK kinases in cells. Treatment with the selective MARK inhibitor MRT199665 caused apoptosis of MEF2C-activated human AML cell lines and primary patient specimens, but not those lacking MEF2C phosphorylation. These findings identify kinase-dependent dysregulation of transcription factor control as a determinant of therapy response in AML, with immediate potential for improved diagnosis and therapy for this disease.

cancer biology↗

bioRxiv2016

Multidimensional imbalances in cortical circuit activity in Fragile-X Syndrome mice

A leading theory for multiple brain disorders, such as schizophrenia and autism, is that they arise from developmental imbalances in excitatory and inhibitory (E/I) brain circuitry. However, it is unclear whether this simple 1-dimensional model is sufficiently rich to capture the set of key alterations of neural circuit processing in brain disorders. Here we used a combination of computational modeling and large-scale analysis of in vivo 2-photon Ca2+ imaging data from somatosensory cortex of wild-type and Fmr1 knock-out (KO) mice, a model of Fragile X syndrome, to test the E/I imbalance model. Our main findings were: 1) the E/I imbalance model was not rich enough to capture the alterations in neural activity statistics in Fmr1 KO mice; 2) in a computational model we found greatly varying magnitudes and directions of effects of synaptic and cellular properties on network activity; 3) evidence for opposite changes in circuit properties of Fmr1 KO mice at different stages of development; 4) a reduction in the entropy of circuit activity in young Fmr1 KO mice compared to wild-type, but an opposite increase in adult Fmr1 KO mice. These findings suggest qualitatively new strategies for developing treatments for Fragile-X Syndrome and related disorders.

neuroscience↗