NDLI: Targeting of mTORC1/2 by the mTOR kinase inhibitor PP242 induces apoptosis in AML cells under conditions mimicking the bone marrow microenvironment

Content Provider	PubMed Central
Author	Zeng, Zhihong Shi, Yue Xi Tsao, Twee Qiu, Yihua Kornblau, Steven M. Baggerly, Keith A. Liu, Wenbin Jessen, Katti Liu, Yi Hagop, Kantarjian Rommel, Christian Fruman, David A. Andreeff, Michael Marina, Konopleva
Copyright Year	2012
Abstract	The interactions between the bone marrow (BM) microenvironment and acute myeloid leukemia (AML) is known to promote survival of AML cells. In this study, we used reverse phase-protein array (RPPA) technology to measure changes in multiple proteins induced by stroma in leukemic cells. We then investigated the potential of an mTOR kinase inhibitor, PP242, to disrupt leukemia/stroma interactions, and examined the effects of PP242 in vivo using a mouse model. Using RPPA, we confirmed that multiple survival signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), were up-regulated in primary AML cells cocultured with stroma. PP242 effectively induced apoptosis in primary samples cultured with or without stroma. Mechanistically, PP242 attenuated the activities of mTORC1 and mTORC2, sequentially inhibited phosphorylated AKT, S6K, and 4EBP1, and concurrently suppressed chemokine receptor CXCR4 expression in primary leukemic cells and in stromal cells cultured alone or cocultured with leukemic cells. In the in vivo leukemia mouse model, PP242 inhibited mTOR signaling in leukemic cells and demonstrated a greater antileukemia effect than rapamycin. Our findings indicate that disrupting mTOR/AKT signaling with a selective mTOR kinase inhibitor can effectively target leukemic cells within the BM microenvironment.
Related Links	http://dx.doi.org/10.1182/blood-2011-11-393934
Ending Page	2689
Page Count	11
Starting Page	2679
File Format	PDF
ISSN	00064971
e-ISSN	15280020
Journal	Blood
Issue Number	13
Volume Number	120
Language	English
Publisher	American Society of Hematology
Publisher Date	2012-09-27
Access Restriction	Open
Rights Holder	American Society of Hematology
Subject Keyword	Immunology Cell Biology Biochemistry Hematology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Hematology Biochemistry Immunology

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