RNAi screen for rapid therapeutic target identification in leukemia patients

Jeffrey Tyner, Michael W. Deininger, Marc Loriaux, Bill Chang, Jason R. Gotli, Stephanie G. Willis, Heidi Erickson, Tibor Kovacsovics, Thomas O'Hare, Michael Heinrich, Brian Druker

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Targeted therapy has vastly improved outcomes in certain types of cancer. Extension of this paradigm across a broad spectrum of malignancies will require an efficient method to determine the molecular vulnerabilities of cancerous cells. Improvements in sequencing technology will soon enable high-throughput sequencing of entire genomes of cancer patients; however, determining the relevance of identified sequence variants will require complementary functional analyses. Here, we report an RNAi-assisted protein target identification (RAPID) technology that individually assesses targeting of each member of the tyrosine kinase gene family. We demonstrate that RAPID screening of primary leukemia cells from 30 patients identifies targets that are critical to survival of the malignant cells from 10 of these individuals. We identify known, activating mutations in JAK2 and K-RAS, as well as patient-specific sensitivity to down-regulation of FLT1, CSF1R, PDGFR, ROR1, EPHA4/5, JAK1/3, LMTK3, LYN, FYN, PTK2B, and N-RAS. We also describe a previously undescribed, somatic, activating mutation in the thrombopoietin receptor that is sensitive to downstream pharmacologic inhibition. Hence, the RAPID technique can quickly identify molecular vulnerabilities in malignant cells. Combination of this technique with whole-genome sequencing will represent an ideal tool for oncogenic target identification such that specific therapies can be matched with individual patients.

Original languageEnglish (US)
Pages (from-to)8695-8700
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number21
DOIs
StatePublished - May 26 2009

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RNA Interference
Leukemia
Thrombopoietin Receptors
Genome
Technology
Neoplasms
Mutation
Proteins
Therapeutics
Protein-Tyrosine Kinases
Cell Survival
Down-Regulation
Genes

Keywords

  • Acute lymphoblastic leukemia
  • Acute myeloid leukemia
  • Chronic myelomonocytic leukemia
  • Molecular diagnosis
  • Personalized medicine

ASJC Scopus subject areas

  • General

Cite this

RNAi screen for rapid therapeutic target identification in leukemia patients. / Tyner, Jeffrey; Deininger, Michael W.; Loriaux, Marc; Chang, Bill; Gotli, Jason R.; Willis, Stephanie G.; Erickson, Heidi; Kovacsovics, Tibor; O'Hare, Thomas; Heinrich, Michael; Druker, Brian.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 21, 26.05.2009, p. 8695-8700.

Research output: Contribution to journalArticle

Tyner, Jeffrey ; Deininger, Michael W. ; Loriaux, Marc ; Chang, Bill ; Gotli, Jason R. ; Willis, Stephanie G. ; Erickson, Heidi ; Kovacsovics, Tibor ; O'Hare, Thomas ; Heinrich, Michael ; Druker, Brian. / RNAi screen for rapid therapeutic target identification in leukemia patients. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 21. pp. 8695-8700.
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