Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription Thomas, Daniel, Powell, Jason A., Vergez, Francois, Segal, David H., Nguyen, Nhu-Y. N., Baker, Adele, Teh, Tse-Chieh, Barry, Emma F., Sarry, Jean-Emmanuel, Lee, Erwin M., Nero, Tracy L., Jabbour, Anissa M., Pomilio, Giovanna, Green, Benjamin D., Manenti, Stephane, Glaser, Stefan P., Parker, Michael W., Lopez, Angel F., Ekert, Paul G., Lock, Richard B., Huang, David C. S., Nilsson, Susie K., Récher, Christian, Wei, Andrew H. and Guthridge, Mark A. 2013, Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription, Blood, vol. 122, no. 5, pp. 738-748, doi: 10.1182/blood-2012-08-447441. Attached Files Name Description MIMEType Size Downloads Title Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription Author(s) Thomas, Daniel Powell, Jason A. Vergez, Francois Segal, David H. Nguyen, Nhu-Y. N. Baker, Adele Teh, Tse-Chieh Barry, Emma F. Sarry, Jean-Emmanuel Lee, Erwin M. Nero, Tracy L. Jabbour, Anissa M. Pomilio, Giovanna Green, Benjamin D. Manenti, Stephane Glaser, Stefan P. Parker, Michael W. Lopez, Angel F. Ekert, Paul G. Lock, Richard B. Huang, David C. S. Nilsson, Susie K. Récher, Christian Wei, Andrew H. Guthridge, Mark A. orcid.org/0000-0002-0536-3471 Journal name Blood Volume number 122 Issue number 5 Start page 738 End page 748 Total pages 11 Publisher American Society of Hematology Place of publication Washington, D.C. Publication date 2013-08-01 ISSN 0006-4971 1528-0020 Summary Resistance to cell death is a hallmark of cancer and renders transformed cells resistant to multiple apoptotic triggers. The Bcl-2 family member, Mcl-1, is a key driver of cell survival in diverse cancers, including acute myeloid leukemia (AML). A screen for compounds that downregulate Mcl-1 identified the kinase inhibitor, PIK-75, which demonstrates marked proapoptotic activity against a panel of cytogenetically diverse primary human AML patient samples. We show that PIK-75 transiently blocks Cdk7/9, leading to transcriptional suppression of MCL-1, rapid loss of Mcl-1 protein, and alleviation of its inhibition of proapoptotic Bak. PIK-75 also targets the p110α isoform of PI3K, which leads to a loss of association between Bcl-xL and Bak. The simultaneous loss of Mcl-1 and Bcl-xL association with Bak leads to rapid apoptosis of AML cells. Concordantly, low Bak expression in AML confers resistance to PIK-75–mediated killing. On the other hand, the induction of apoptosis by PIK-75 did not require the expression of the BH3 proteins Bim, Bid, Bad, Noxa, or Puma. PIK-75 significantly reduced leukemia burden and increased the survival of mice engrafted with human AML without inducing overt toxicity. Future efforts to cotarget PI3K and Cdk9 with drugs such as PIK-75 in AML are warranted. Language eng DOI 10.1182/blood-2012-08-447441 Indigenous content off Field of Research 1102 Cardiorespiratory Medicine and Haematology 1103 Clinical Sciences 1114 Paediatrics and Reproductive Medicine HERDC Research category C1.1 Refereed article in a scholarly journal Persistent URL http://hdl.handle.net/10536/DRO/DU:30132348 Document type: Journal Article Collections: Faculty of Science, Engineering and Built Environment School of Life and Environmental Sciences Related Links Link Description Connect to published version Go to link with your DU access privileges     Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved. Versions Version Filter Type Thu, 21 Nov 2019, 14:33:48 EST Fri, 22 Nov 2019, 04:04:52 EST Mon, 25 Nov 2019, 14:32:07 EST Tue, 26 Nov 2019, 05:04:26 EST Thu, 28 Nov 2019, 13:26:38 EST Thu, 28 Nov 2019, 13:32:42 EST Thu, 12 Dec 2019, 16:35:32 EST Sun, 28 Feb 2021, 18:35:33 EST Filtered Full Citation counts:   Cited 42 times in TR Web of Science Cited 0 times in Scopus Search Google Scholar Access Statistics: 141 Abstract Views, 1 File Downloads  -  Detailed Statistics Created: Mon, 25 Nov 2019, 14:32:07 EST

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