Molecular approaches to understanding the functional circuitry of the nervous system promise new insights into the relationship between genes, brain and behaviour. The cellular diversity of the brain necessitates a cellular resolution approach towards understanding the functional genomics of the nervous system. We describe here an anatomically comprehensive digital atlas containing the expression patterns of approximately 20,000 genes in the adult mouse brain. Data were generated using automated high-throughput procedures for in situ hybridization and data acquisition, and are publicly accessible online. Newly developed image-based informatics tools allow global genome-scale structural analysis and cross-correlation, as well as identification of regionally enriched genes. Unbiased fine-resolution analysis has identified highly specific cellular markers as well as extensive evidence of cellular heterogeneity not evident in classical neuroanatomical atlases. This highly standardized atlas provides an open, primary data resource for a wide variety of further studies concerning brain organization and function.

IntroductionStat3 is a critical signaling intermediate in hematopoietic cells that is activated by recruitment to tyrosine-phosphorylated receptor complexes, including the granulocyte colony-stimulating factor (G-CSF) receptor. Recruitment leads to phosphorylation of Stat3 on tyrosine 705 (pY705), tail-to-tail dimerization, nuclear accumulation, and gene transcription. Recruitment and dimerization require interactions between the Stat3 Src homology 2 (SH2) domain and pY peptide motifs located within receptor complexes or within Stat3, respectively. Stat3-responsive genes include antiapoptosis genes, cell cycle regulators, and angiogenesis factors. Gene activation is enhanced by S727 phosphorylation and appears to be required for accumulation of Stat3 within mitochondria, where it promotes oxidative phosphorylation. 1 The evidence that Stat3 signaling plays a key role in cancer was first obtained from cells transformed by the oncogene v-src. 2 Subsequently, several other oncoproteins that activate tyrosine kinase pathways were shown to result in constitutive Stat3 activation. 3 Fibroblasts expressing a constitutively active Stat3 mutant (Stat3-C) developed malignant properties in culture and formed tumors in nude mice. 4 Clinically, constitutively active Stat3 was first demonstrated in squamous cell carcinoma of the head and neck 5 and since has been demonstrated in many different cancers, including acute myeloid leukemia (AML), [6][7][8] although notably no studies have been done with pediatric patients. As in other malignancies, the finding of constitutive Stat3 activity in AML is associated with poor prognosis, 6 possibly as a result of increased resistance to chemotherapy. Indeed, recent studies have demonstrated that acquired resistance to tyrosine kinase inhibitors (TKI) can be attributed in some cases to increased activity of the Stat3 pathway, and Stat3 inhibition restores TKI sensitivity. 9,10 Given that Stat3 activity is an important factor in malignant behavior and chemoresistance, a variety of approaches have been undertaken to target Stat3. Such studies consistently have shown the ability to reduce tumor cell growth in vitro and in xenograft models. Most of the work targeting Stat3 has focused on epithelial cancers, whereas therapeutic targeting strategies for AML have been directed at tyrosine kinases, including Src, Flt3, and c-kit. Certainly small-molecule TKIs, such as imatinib mesylate and other newer drugs, have proven remarkably effective in many cases; nevertheless, resistance remains a difficult problem. Therefore, new approaches for blocking signaling pathways are needed. Stat3 is an attractive target because the protein itself is not mutated, but rather it mediates abnormal signaling because of a variety of different upstream genetic and/or epigenetic changes.In this study, we report the prevalence of constitutive and G-CSF-induced tyrosine-phosphorylated Stat3 in a panel of AML cell lines and a cohort of primary pediatric AML samples, and the effects of Stat3 inhibition on AML cell growth...

Key Points• In pediatric AML, patterns of Stat3 activation by G-CSF and IL-6 can be identified that are associated with survival.• Such functional information may be useful for risk assessment and for determining which patients may benefit from alternative therapies.

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