MICROARRAY ANALYSIS OF EWS/FLI IN EWING'S SARCOMA REVEALS A CRITICAL ROLE FOR NKX2.2 IN ONCOGENESIS Stephen Lessnick, MD, PhD Division of Pediatric Hematology/Oncology.

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Presentation transcript:

MICROARRAY ANALYSIS OF EWS/FLI IN EWING'S SARCOMA REVEALS A CRITICAL ROLE FOR NKX2.2 IN ONCOGENESIS Stephen Lessnick, MD, PhD Division of Pediatric Hematology/Oncology Department of Oncological Sciences Huntsman Cancer Institute University of Utah

EWS/FLI is an Aberrant Trancription Factor What genes are regulated by EWS/FLI in Ewing’s sarcoma? What role do those genes play in Ewing’s sarcoma development?

What’s the right model? Kovar Semin Cancer Biol 2005

EWS/FLI Function in Ewing’s Sarcoma Cells EWS FLI RNAi against EWS/FLI EWS FLI reintroduce EWS/FLI patient-derived Ewing’s sarcoma cell lines

EWS/FLI Knockdown

EWS/FLI RNAi Inhibits Transformation

Expression Profiling of A673/RNAi ~ genes upregulated by EWS/FLI ~ genes downregulated by EWS/FLI Developed a library of retroviral- RNAi constructs targeting each of the EWS/FLI- upregulated genes. Screening for growth and transformation effects. NKX2.2 was one of the first “hits”

NKX2.2 Involved in CNS development Involved in pancreatic islet development Involved in oligodendrocyte development Regulated by Sonic Hedgehog in CNS

Knockdown of NKX2.2

NKX2.2 is Necessary for Oncogenic Transformation While NKX is necessary, it is not sufficient for transformation

NKX2.2 as a Potential Marker for Ewing’s Sarcoma

Questions to address Regulation of NKX2.2 by EWS/FLI Regulation of NKX2.2 by EWS/FLI Molecular details of NKX2.2 function Molecular details of NKX2.2 function NKX2.2 target genes NKX2.2 target genes Role of NKX2.2 targets in transformed phenotype Role of NKX2.2 targets in transformed phenotype NKX2.2 as a diagnostic and/or prognostic factor in Ewing’s sarcoma NKX2.2 as a diagnostic and/or prognostic factor in Ewing’s sarcoma Opportunities for therapeutic targeting Opportunities for therapeutic targeting

Lessnick lab Tonya Avery Kunal Gangwal Jeff Hancock Michelle Kinsey Leah Owen Richard Smith Chi Braunreiter Cheryl Coffin Chris Denny Todd Golub Andrew Kung Dick Lemons Ed McCabe Lor Randall -NIH/NCI K08 -American Cancer Society -Terri Anna Perine Sarcoma Fund -PCMC Foundation -Hope Street Kids -Huntsman Cancer Foundation -Department of Pediatrics, U of Utah