Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma [microarray]

Drugs that modify the epigenome are powerful tools for treating cancer, but these drugs often have pleiotropic effects, and identifying patients who will benefit from them remains a major clinical challenge. Here we show that medulloblastomas driven by the transcription factor Gfi1 are exquisitely dependent on the enzyme lysine demethylase 1 (Kdm1a/Lsd1). We demonstrate that Lsd1 physically associates with Gfi1, and that these proteins cooperate to inhibit genes involved in neuronal commitment and differentiation. We also show that Lsd1 is essential for Gfi1-mediated transformation: Gfi1 proteins that cannot recruit Lsd1 are unable to drive tumorigenesis and genetic ablation of Lsd1 markedly impairs tumor growth in vivo. Finally, pharmacological inhibitors of Lsd1 potently inhibit growth of Gfi1-driven tumors. These studies provide important insight into the mechanisms by which Gfi1 contributes to tumorigenesis, and identify Lsd1 inhibitors as promising therapeutic agents for Gfi1-driven medulloblastoma. Affymetrix GeneChip Mouse Genome 430 2.0 Array profiling was conducted on n=7 MG (Myc/Gfi1) murine medulloblastomas. This data was compared to the previously published expression array data generated from n=5 NSC (neural stem cell) samples [GSM842157-GSM842161] deposited in GEO Series GSE34126. MG medulloblastoma tumors were surgically resected, frozen, and subsequently subjected to RNA extraction for downstream Affymetrix expression array profiling. The complete dataset representing: (1) the MG tumor Samples and (2) the NSCs Samples [GSM842157-GSM842161] from Series GSE34126 (re-processed using RMA), is linked below as a supplementary file.