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- W2562340897 abstract "Characterization of the genomic landscapes of cancer with new technologies, such as massively parallel sequencing, has catapulted our understanding of human malignancies. However, many questions remain about the true genetic dependencies in human cancer, and for most malignancies, therapeutic impact has lagged behind the unraveling of the DNA code. In principle, the integration of functional and chemical genomics offers a powerful approach to decipher the mechanisms of cancer and inform therapeutics. We have applied such as integrative approach to the identification of new targeted strategies to induce the differentiation of acute myeloid leukemia (AML) cells. Targeting PML-RARα, the fusion protein present in the majority of patients diagnosed with acute promyelocytic leukemia (APL), demonstrated feasible the use of targeted differentiation therapy in this AML subtype. Emerging data support a role not only for transcription factor-directed therapy, but also for kinase-directed therapy, to induce AML differentiation. In a recent clinical trial the FMS-like tyrosine kinase 3 (FLT3) inhibitor quizartinib induced differentiation in patients with FLT3-ITD-positive AML, leading to responses in the majority of patients receiving the drug. Moreover, newer agents targeting chromatin regulators (e.g., DOT1L and BRD4) have been demonstrated to induce AML differentiation in vitro and in vivo, lending additional support to the potential of differentiation therapy for this disease. We have applied chemical and functional genomic screens for small-molecule and shRNA inducers of a complex gene expression signature of differentiation. Two high priority metabolic targets emerged at the intersection of these screens and have been validated in AML cells in vitro and in vivo with chemical and genetic perturbagens. Citation Format: Kimberly Stegmaier. Integrating chemical and functional genomics for leukemia discovery. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA23." @default.
- W2562340897 created "2017-01-06" @default.
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- W2562340897 date "2015-08-19" @default.
- W2562340897 modified "2023-09-27" @default.
- W2562340897 title "Abstract IA23: Integrating chemical and functional genomics for leukemia discovery." @default.
- W2562340897 doi "https://doi.org/10.1158/1557-3265.hemmal14-ia23" @default.
- W2562340897 hasPublicationYear "2015" @default.
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