Mechanisms of apoptosis induction by simultaneous inhibition of PI3K and FLT3-ITD in AML cells in the hypoxic bone marrow microenvironment

Linhua Jin; Yoko Tabe; Hongbo Lu; Gautam Borthakur; Takashi Miida; Hagop Kantarjian; Michael Andreeff; Marina Konopleva

doi:10.1016/j.canlet.2012.09.020

Mechanisms of apoptosis induction by simultaneous inhibition of PI3K and FLT3-ITD in AML cells in the hypoxic bone marrow microenvironment

Linhua Jin, Yoko Tabe, Hongbo Lu, Gautam Borthakur, Takashi Miida, Hagop Kantarjian, Michael Andreeff, Marina Konopleva

Leukemia

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

We investigated the antileukemia effects and molecular mechanisms of apoptosis induction by simultaneous blockade of PI3K and mutant FLT3 in AML cells grown under hypoxia in co-cultures with bone marrow stromal cells. Combined treatment with selective class I PI3K inhibitor GDC-0941 and sorafenib reversed the protective effects of bone marrow stromal cells on FLT3-mutant AML cells in hypoxia, which was associated with downregulation of Pim-1 and Mcl-1 expression levels. These findings suggest that combined inhibition of PI3K and FLT3-ITD may constitute a targeted approach to eradicating chemoresistant AML cells sequestered in hypoxic bone marrow niches.

Original language	English (US)
Pages (from-to)	45-58
Number of pages	14
Journal	Cancer Letters
Volume	329
Issue number	1
DOIs	https://doi.org/10.1016/j.canlet.2012.09.020
State	Published - Feb 1 2013

Keywords

Acute myeloid leukemia
Bone marrow microenvironment
GDC-0941
Hypoxia
Sorafenib

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1016/j.canlet.2012.09.020

Cite this

@article{7420274bd2f64dc2b8723901a68e8f3e,

title = "Mechanisms of apoptosis induction by simultaneous inhibition of PI3K and FLT3-ITD in AML cells in the hypoxic bone marrow microenvironment",

abstract = "We investigated the antileukemia effects and molecular mechanisms of apoptosis induction by simultaneous blockade of PI3K and mutant FLT3 in AML cells grown under hypoxia in co-cultures with bone marrow stromal cells. Combined treatment with selective class I PI3K inhibitor GDC-0941 and sorafenib reversed the protective effects of bone marrow stromal cells on FLT3-mutant AML cells in hypoxia, which was associated with downregulation of Pim-1 and Mcl-1 expression levels. These findings suggest that combined inhibition of PI3K and FLT3-ITD may constitute a targeted approach to eradicating chemoresistant AML cells sequestered in hypoxic bone marrow niches.",

keywords = "Acute myeloid leukemia, Bone marrow microenvironment, GDC-0941, Hypoxia, Sorafenib",

author = "Linhua Jin and Yoko Tabe and Hongbo Lu and Gautam Borthakur and Takashi Miida and Hagop Kantarjian and Michael Andreeff and Marina Konopleva",

note = "Funding Information: This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture of Japan and Juntendo Institutional Research Grant of Environmental and Gender Specific Medicine(to Y.T.); Juntendo Institutional Project Research Program (to L.J.); 1R01CA155056-01, CDP-01, Leukemia and Lymphoma Society and DRP, Leukemia Spore 5 P50 CA100632-08 (to M.K.); and 5P01 CA55164-17 (to M.A.). ",

year = "2013",

month = feb,

day = "1",

doi = "10.1016/j.canlet.2012.09.020",

language = "English (US)",

volume = "329",

pages = "45--58",

journal = "Cancer Letters",

issn = "0304-3835",

publisher = "Elsevier Ireland Ltd",

number = "1",

}

TY - JOUR

T1 - Mechanisms of apoptosis induction by simultaneous inhibition of PI3K and FLT3-ITD in AML cells in the hypoxic bone marrow microenvironment

AU - Jin, Linhua

AU - Tabe, Yoko

AU - Lu, Hongbo

AU - Borthakur, Gautam

AU - Miida, Takashi

AU - Kantarjian, Hagop

AU - Andreeff, Michael

AU - Konopleva, Marina

N1 - Funding Information: This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture of Japan and Juntendo Institutional Research Grant of Environmental and Gender Specific Medicine(to Y.T.); Juntendo Institutional Project Research Program (to L.J.); 1R01CA155056-01, CDP-01, Leukemia and Lymphoma Society and DRP, Leukemia Spore 5 P50 CA100632-08 (to M.K.); and 5P01 CA55164-17 (to M.A.).

PY - 2013/2/1

Y1 - 2013/2/1

N2 - We investigated the antileukemia effects and molecular mechanisms of apoptosis induction by simultaneous blockade of PI3K and mutant FLT3 in AML cells grown under hypoxia in co-cultures with bone marrow stromal cells. Combined treatment with selective class I PI3K inhibitor GDC-0941 and sorafenib reversed the protective effects of bone marrow stromal cells on FLT3-mutant AML cells in hypoxia, which was associated with downregulation of Pim-1 and Mcl-1 expression levels. These findings suggest that combined inhibition of PI3K and FLT3-ITD may constitute a targeted approach to eradicating chemoresistant AML cells sequestered in hypoxic bone marrow niches.

AB - We investigated the antileukemia effects and molecular mechanisms of apoptosis induction by simultaneous blockade of PI3K and mutant FLT3 in AML cells grown under hypoxia in co-cultures with bone marrow stromal cells. Combined treatment with selective class I PI3K inhibitor GDC-0941 and sorafenib reversed the protective effects of bone marrow stromal cells on FLT3-mutant AML cells in hypoxia, which was associated with downregulation of Pim-1 and Mcl-1 expression levels. These findings suggest that combined inhibition of PI3K and FLT3-ITD may constitute a targeted approach to eradicating chemoresistant AML cells sequestered in hypoxic bone marrow niches.

KW - Acute myeloid leukemia

KW - Bone marrow microenvironment

KW - GDC-0941

KW - Hypoxia

KW - Sorafenib

UR - http://www.scopus.com/inward/record.url?scp=84871720541&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84871720541&partnerID=8YFLogxK

U2 - 10.1016/j.canlet.2012.09.020

DO - 10.1016/j.canlet.2012.09.020

M3 - Article

C2 - 23036488

AN - SCOPUS:84871720541

SN - 0304-3835

VL - 329

SP - 45

EP - 58

JO - Cancer Letters

JF - Cancer Letters

IS - 1

ER -

Mechanisms of apoptosis induction by simultaneous inhibition of PI3K and FLT3-ITD in AML cells in the hypoxic bone marrow microenvironment

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this