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 language | English |
|---|---|
| Pages (from-to) | 1266-1276 |
| Number of pages | 11 |
| Journal | Leukemia |
| Volume | 26 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 2012 Jun 1 |
| Externally published | Yes |
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Keywords
- acute myeloid leukemia
- cell cycle
- checkpoint
- genomics
- shRNA screen
- WEE1
ASJC Scopus subject areas
- Hematology
- Cancer Research
- Anesthesiology and Pain Medicine
Cite this
Integrated genomic analyses identify WEE1 as a critical mediator of cell fate and a novel therapeutic target in acute myeloid leukemia. / Porter, C. C.; Kim, J.; Fosmire, S.; Gearheart, C. M.; Van Linden, A.; Baturin, D.; Zaberezhnyy, V.; Patel, P. R.; Gao, D.; Tan, Aik-Choon; Degregori, J.
In: Leukemia, Vol. 26, No. 6, 01.06.2012, p. 1266-1276.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Integrated genomic analyses identify WEE1 as a critical mediator of cell fate and a novel therapeutic target in acute myeloid leukemia
AU - Porter, C. C.
AU - Kim, J.
AU - Fosmire, S.
AU - Gearheart, C. M.
AU - Van Linden, A.
AU - Baturin, D.
AU - Zaberezhnyy, V.
AU - Patel, P. R.
AU - Gao, D.
AU - Tan, Aik-Choon
AU - Degregori, J.
PY - 2012/6/1
Y1 - 2012/6/1
N2 - 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.
AB - 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.
KW - acute myeloid leukemia
KW - cell cycle
KW - checkpoint
KW - genomics
KW - shRNA screen
KW - WEE1
UR - http://www.scopus.com/inward/record.url?scp=84861999101&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84861999101&partnerID=8YFLogxK
U2 - 10.1038/leu.2011.392
DO - 10.1038/leu.2011.392
M3 - Article
C2 - 22289989
AN - SCOPUS:84861999101
VL - 26
SP - 1266
EP - 1276
JO - Leukemia
JF - Leukemia
SN - 0887-6924
IS - 6
ER -