Abstract
The serine/threonine kinase AMP-activated protein kinase (AMPK) and its downstream effectors, including endothelial nitric oxide synthase and BCL-2, are hyperactivated in B-cell precursor-acute lymphoblastic leukemia (BCP-ALL) cells with MLL gene rearrangements. We investigated the role of activated AMPK in supporting leukemic cell survival and evaluated AMPK as a potential drug target. Exposure of leukemic cells to the commercial AMPK inhibitor compound C resulted in massive apoptosis only in cells with MLL gene rearrangements. These results were confirmed by targeting AMPK with specific short hairpin RNAs. Compound C-induced apoptosis was associated with mitochondrial membrane depolarization, reactive oxygen species production, cytochrome c release and caspases cleavage, indicating intrinsic apoptosis pathway activation. Treatment with low concentrations of compound C resulted in a strong antileukemic activity, together with cytochrome c release and cleavage of caspases and poly(ADP-ribose) polymerase, also in MLL-rearranged primary BCP-ALL samples. Moreover, AMPK inhibition in MLL-rearranged cell lines synergistically enhanced the antiproliferative effects of vincristine, daunorubicin, cytarabine, dexamethasone and L-asparaginase in most of the evaluated conditions. Taken together, these results indicate that the activation of the AMPK pathway directly contributes to the survival of MLL-rearranged BCP-ALL cells and AMPK inhibitors could represent a new therapeutic strategy for this high-risk leukemia.
| Original language | English |
|---|---|
| Pages (from-to) | 1019-1027 |
| Number of pages | 9 |
| Journal | Leukemia |
| Volume | 27 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 2013 |
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Keywords
- acute lymphoblastic leukemia
- AMPK
- apoptosis
- MLL rearrangements
ASJC Scopus subject areas
- Hematology
- Cancer Research
- Anesthesiology and Pain Medicine
Cite this
AMPK inhibition enhances apoptosis in MLL-rearranged pediatric B-acute lymphoblastic leukemia cells. / Accordi, B.; Galla, L.; Milani, G.; Curtarello, M.; Serafin, V.; Lissandron, V.; Viola, G.; Te Kronnie, G.; De Maria, R.; Petricoin, E. F.; Liotta, L. A.; Indraccolo, S.; Basso, G.
In: Leukemia, Vol. 27, No. 5, 05.2013, p. 1019-1027.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - AMPK inhibition enhances apoptosis in MLL-rearranged pediatric B-acute lymphoblastic leukemia cells
AU - Accordi, B.
AU - Galla, L.
AU - Milani, G.
AU - Curtarello, M.
AU - Serafin, V.
AU - Lissandron, V.
AU - Viola, G.
AU - Te Kronnie, G.
AU - De Maria, R.
AU - Petricoin, E. F.
AU - Liotta, L. A.
AU - Indraccolo, S.
AU - Basso, G.
PY - 2013/5
Y1 - 2013/5
N2 - The serine/threonine kinase AMP-activated protein kinase (AMPK) and its downstream effectors, including endothelial nitric oxide synthase and BCL-2, are hyperactivated in B-cell precursor-acute lymphoblastic leukemia (BCP-ALL) cells with MLL gene rearrangements. We investigated the role of activated AMPK in supporting leukemic cell survival and evaluated AMPK as a potential drug target. Exposure of leukemic cells to the commercial AMPK inhibitor compound C resulted in massive apoptosis only in cells with MLL gene rearrangements. These results were confirmed by targeting AMPK with specific short hairpin RNAs. Compound C-induced apoptosis was associated with mitochondrial membrane depolarization, reactive oxygen species production, cytochrome c release and caspases cleavage, indicating intrinsic apoptosis pathway activation. Treatment with low concentrations of compound C resulted in a strong antileukemic activity, together with cytochrome c release and cleavage of caspases and poly(ADP-ribose) polymerase, also in MLL-rearranged primary BCP-ALL samples. Moreover, AMPK inhibition in MLL-rearranged cell lines synergistically enhanced the antiproliferative effects of vincristine, daunorubicin, cytarabine, dexamethasone and L-asparaginase in most of the evaluated conditions. Taken together, these results indicate that the activation of the AMPK pathway directly contributes to the survival of MLL-rearranged BCP-ALL cells and AMPK inhibitors could represent a new therapeutic strategy for this high-risk leukemia.
AB - The serine/threonine kinase AMP-activated protein kinase (AMPK) and its downstream effectors, including endothelial nitric oxide synthase and BCL-2, are hyperactivated in B-cell precursor-acute lymphoblastic leukemia (BCP-ALL) cells with MLL gene rearrangements. We investigated the role of activated AMPK in supporting leukemic cell survival and evaluated AMPK as a potential drug target. Exposure of leukemic cells to the commercial AMPK inhibitor compound C resulted in massive apoptosis only in cells with MLL gene rearrangements. These results were confirmed by targeting AMPK with specific short hairpin RNAs. Compound C-induced apoptosis was associated with mitochondrial membrane depolarization, reactive oxygen species production, cytochrome c release and caspases cleavage, indicating intrinsic apoptosis pathway activation. Treatment with low concentrations of compound C resulted in a strong antileukemic activity, together with cytochrome c release and cleavage of caspases and poly(ADP-ribose) polymerase, also in MLL-rearranged primary BCP-ALL samples. Moreover, AMPK inhibition in MLL-rearranged cell lines synergistically enhanced the antiproliferative effects of vincristine, daunorubicin, cytarabine, dexamethasone and L-asparaginase in most of the evaluated conditions. Taken together, these results indicate that the activation of the AMPK pathway directly contributes to the survival of MLL-rearranged BCP-ALL cells and AMPK inhibitors could represent a new therapeutic strategy for this high-risk leukemia.
KW - acute lymphoblastic leukemia
KW - AMPK
KW - apoptosis
KW - MLL rearrangements
UR - http://www.scopus.com/inward/record.url?scp=84877614687&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84877614687&partnerID=8YFLogxK
U2 - 10.1038/leu.2012.338
DO - 10.1038/leu.2012.338
M3 - Article
C2 - 23228943
AN - SCOPUS:84877614687
VL - 27
SP - 1019
EP - 1027
JO - Leukemia
JF - Leukemia
SN - 0887-6924
IS - 5
ER -