Integrated genomic analyses identify WEE1 as a critical mediator of cell fate and a novel therapeutic target in acute myeloid leukemia

C. C. Porter, J. Kim, S. Fosmire, C. M. Gearheart, A. Van Linden, D. Baturin, V. Zaberezhnyy, P. R. Patel, D. Gao, Aik-Choon Tan, J. Degregori

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44 Citations (Scopus)

Abstract

Acute myeloid leukemia (AML) remains a therapeutic challenge despite increasing knowledge about the molecular origins of the disease, as the mechanisms of AML cell escape from chemotherapy remain poorly defined. We hypothesized that AML cells are addicted to molecular pathways in the context of chemotherapy and used complementary approaches to identify these addictions. Using novel molecular and computational approaches, we performed genome-wide short-hairpin RNA screens to identify proteins that mediate AML cell fate after cytarabine exposure; gene expression profiling of AML cells exposed to cytarabine to identify genes with induced expression in this context; and examination of existing gene expression data from primary patient samples. Integration of these independent analyses strongly implicates cell-cycle checkpoint proteins, particularly WEE1, as critical mediators of AML cell survival after cytarabine exposure. Knockdown of WEE1 in a secondary screen confirmed its role in AML cell survival. Pharmacologic inhibition of WEE1 in AML cell lines and primary cells is synergistic with cytarabine. Further experiments demonstrate that inhibition of WEE1 prevents S-phase arrest induced by cytarabine, broadening the functions of WEE1 that may be exploited therapeutically. These data highlight the power of integrating functional and descriptive genomics, and identify WEE1 as a potential therapeutic target in AML.

Original languageEnglish
Pages (from-to)1266-1276
Number of pages11
JournalLeukemia
Volume26
Issue number6
DOIs
Publication statusPublished - 2012 Jun 1
Externally publishedYes

Keywords

  • acute myeloid leukemia
  • cell cycle
  • checkpoint
  • genomics
  • shRNA screen
  • WEE1

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

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    Porter, C. C., Kim, J., Fosmire, S., Gearheart, C. M., Van Linden, A., Baturin, D., Zaberezhnyy, V., Patel, P. R., Gao, D., Tan, A-C., & Degregori, J. (2012). Integrated genomic analyses identify WEE1 as a critical mediator of cell fate and a novel therapeutic target in acute myeloid leukemia. Leukemia, 26(6), 1266-1276. https://doi.org/10.1038/leu.2011.392