Activation of integrin-linked kinase is a critical prosurvival pathway induced in leukemic cells by bone marrow-derived stromal cells

Yoko Tabe, Linhua Jin, Yuko Tsutsumi-Ishii, Yuanyuan Xu, Teresa McQueen, Waldemar Priebe, Gordon Mills, Akimichi Ohsaka, Isao Nagaoka, Michael Andreeff, Marina Konopleva

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Abstract

Integrin-linked kinase (ILK) directly interacts with β integrins and phosphorylates Akt in a phosphatidylinositol 3-kinase (PI3K)-dependent manner. In this study, we examined the functional role of ILK activation in leukemic and bone marrow stromal cells on their direct contact. Coculture of leukemic NB4 cells with bone marrow-derived stromal mesenchymal stem cells (MSC) resulted in robust activation of multiple signaling pathways, including ILK/Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), signal transducers and activators of transcription 3 (STAT3), and Notch1/Hes. Blockade of PI3K or ILK signaling with pharmacologic inhibitors LY294002 or QLT0267 specifically inhibited stroma-induced phosphorylation of Akt and glycogen synthase kinase 3β, suppressed STAT3 and EKK1/2 activation, and decreased Notch1 and Hes1 expression in leukemic cells. This resulted in induction of apoptosis in both leukemic cell lines and in primary acute myelogenous leukemia samples that was not abrogated by MSC coculture. In turn, leukemic cells growing in direct contact with bone marrow stromal elements induce activation of Akt, ERK1/2, and STAT3 signaling in MSC, accompanied by significant increase in Hes1 and Bcl-2 proteins, which were all suppressed by QLT0267 and LY294002. In summary, our results indicate reciprocal activation of ILK/Akt in both leukemic and bone marrow stromal cells. We propose that ILK/Akt is a proximal signaling pathway critical for survival of leukemic cells within the bone marrow microenvironment. Hence, disruption of these interactions by ILK inhibitors represents a potential novel therapeutic strategy to eradicate leukemia in the bone marrow microenvironment by simultaneous targeting of both leukemic cells and activated bone marrow stromal cells.

Original languageEnglish (US)
Pages (from-to)684-694
Number of pages11
JournalCancer Research
Volume67
Issue number2
DOIs
StatePublished - Jan 15 2007
Externally publishedYes

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Critical Pathways
Mesenchymal Stromal Cells
STAT3 Transcription Factor
Phosphatidylinositol 3-Kinase
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Coculture Techniques
Bone Marrow Cells
Bone Marrow
Glycogen Synthase Kinase 3
integrin-linked kinase
Acute Myeloid Leukemia
Integrins
Leukemia
Phosphorylation
Apoptosis
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Activation of integrin-linked kinase is a critical prosurvival pathway induced in leukemic cells by bone marrow-derived stromal cells. / Tabe, Yoko; Jin, Linhua; Tsutsumi-Ishii, Yuko; Xu, Yuanyuan; McQueen, Teresa; Priebe, Waldemar; Mills, Gordon; Ohsaka, Akimichi; Nagaoka, Isao; Andreeff, Michael; Konopleva, Marina.

In: Cancer Research, Vol. 67, No. 2, 15.01.2007, p. 684-694.

Research output: Contribution to journalArticle

Tabe, Y, Jin, L, Tsutsumi-Ishii, Y, Xu, Y, McQueen, T, Priebe, W, Mills, G, Ohsaka, A, Nagaoka, I, Andreeff, M & Konopleva, M 2007, 'Activation of integrin-linked kinase is a critical prosurvival pathway induced in leukemic cells by bone marrow-derived stromal cells', Cancer Research, vol. 67, no. 2, pp. 684-694. https://doi.org/10.1158/0008-5472.CAN-06-3166
Tabe, Yoko ; Jin, Linhua ; Tsutsumi-Ishii, Yuko ; Xu, Yuanyuan ; McQueen, Teresa ; Priebe, Waldemar ; Mills, Gordon ; Ohsaka, Akimichi ; Nagaoka, Isao ; Andreeff, Michael ; Konopleva, Marina. / Activation of integrin-linked kinase is a critical prosurvival pathway induced in leukemic cells by bone marrow-derived stromal cells. In: Cancer Research. 2007 ; Vol. 67, No. 2. pp. 684-694.
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AU - Tabe, Yoko

AU - Jin, Linhua

AU - Tsutsumi-Ishii, Yuko

AU - Xu, Yuanyuan

AU - McQueen, Teresa

AU - Priebe, Waldemar

AU - Mills, Gordon

AU - Ohsaka, Akimichi

AU - Nagaoka, Isao

AU - Andreeff, Michael

AU - Konopleva, Marina

PY - 2007/1/15

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AB - Integrin-linked kinase (ILK) directly interacts with β integrins and phosphorylates Akt in a phosphatidylinositol 3-kinase (PI3K)-dependent manner. In this study, we examined the functional role of ILK activation in leukemic and bone marrow stromal cells on their direct contact. Coculture of leukemic NB4 cells with bone marrow-derived stromal mesenchymal stem cells (MSC) resulted in robust activation of multiple signaling pathways, including ILK/Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), signal transducers and activators of transcription 3 (STAT3), and Notch1/Hes. Blockade of PI3K or ILK signaling with pharmacologic inhibitors LY294002 or QLT0267 specifically inhibited stroma-induced phosphorylation of Akt and glycogen synthase kinase 3β, suppressed STAT3 and EKK1/2 activation, and decreased Notch1 and Hes1 expression in leukemic cells. This resulted in induction of apoptosis in both leukemic cell lines and in primary acute myelogenous leukemia samples that was not abrogated by MSC coculture. In turn, leukemic cells growing in direct contact with bone marrow stromal elements induce activation of Akt, ERK1/2, and STAT3 signaling in MSC, accompanied by significant increase in Hes1 and Bcl-2 proteins, which were all suppressed by QLT0267 and LY294002. In summary, our results indicate reciprocal activation of ILK/Akt in both leukemic and bone marrow stromal cells. We propose that ILK/Akt is a proximal signaling pathway critical for survival of leukemic cells within the bone marrow microenvironment. Hence, disruption of these interactions by ILK inhibitors represents a potential novel therapeutic strategy to eradicate leukemia in the bone marrow microenvironment by simultaneous targeting of both leukemic cells and activated bone marrow stromal cells.

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