NTRK2 activation cooperates with PTEN deficiency in T-ALL through activation of both the PI3K-AKT and JAK-STAT3 pathways.
Loss of PTEN, a negative regulator of the phosphoinositide 3-kinase signaling pathway, is a frequent event in T-cell acute lymphoblastic leukemia, suggesting the importance of phosphoinositide 3-kinase activity in this disease. Indeed, hyperactivation of the phosphoinositide 3-kinase pathway is associated with the disease aggressiveness, poor prognosis and resistance to current therapies. To identify a molecular pathway capable of cooperating with PTEN deficiency to drive oncogenic transformation of leukocytes, we performed an unbiased transformation screen with a library of tyrosine kinases. We found that activation of NTRK2 is able to confer a full growth phenotype of Ba/F3 cells in an IL3-independent manner in the PTEN-null setting. NTRK2 activation cooperates with PTEN deficiency through engaging both phosphoinositide3-kinase/AKT and JAK/STAT3 pathway activation in leukocytes. Notably, pharmacological inhibition demonstrated that p110α and p110δ are the major isoforms mediating the phosphoinositide 3-kinase/AKT signaling driven by NTRK2 activation in PTEN-deficient leukemia cells. Furthermore, combined inhibition of phosphoinositide 3-kinase and STAT3 significantly suppressed proliferation of PTEN-mutant T-cell acute lymphoblastic leukemia both in culture and in mouse xenografts. Together, our data suggest that a unique conjunction of PTEN deficiency and NTRK2 activation in T-cell acute lymphoblastic leukemia, and combined pharmacologic inhibition of phosphoinositide 3-kinase and STAT3 signaling may serve as an effective and durable therapeutic strategy for T-cell acute lymphoblastic leukemia.
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Haluk
H
Yuzugullu
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Thanh
T
Von
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Lauren M
LM
Thorpe
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Sarah R
SR
Walker
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Thomas M
TM
Roberts
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
David A
DA
Frank
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Jean J
JJ
Zhao
NTRK2; PI3K; PTEN; STAT-3; T-ALL; targeted therapy
Nat Genet. 2013 Aug;45(8):927-32
23817572
Mol Cancer Ther. 2006 Oct;5(10):2512-21
17041095
Leukemia. 2009 Aug;23 (8):1417-25
19340001
Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12419-24
9356464
Blood. 2009 Feb 26;113(9):2028-37
19059881
Proc Natl Acad Sci U S A. 2014 Apr 29;111(17 ):6395-400
24737887
Blood. 2005 Jun 1;105(11):4429-36
15657181
Gastroenterol Clin Biol. 1989 May;13(5):469-72
2666238
J Exp Med. 1999 Mar 1;189(5):865-70
10049950
Cancer Cell. 2012 Dec 11;22(6):796-811
23238015
J Clin Invest. 2014 Apr;124(4):1794-809
24569456
Cancer Discov. 2012 May;2(5):425-33
22588880
Nat Rev Cancer. 2015 Jan;15(1):7-24
25533673
Adv Enzyme Regul. 1984;22:27-55
6382953
Genes Dev. 2000 Feb 15;14 (4):391-6
10691731
Blood. 2009 Jul 16;114(3):647-50
19458356
N Engl J Med. 2014 Mar 13;370(11):1061-2
24620870
Cancer Discov. 2012 Oct;2(10):934-47
22961667
J Med Chem. 2013 Jun 13;56(11):4597-610
23662903
Cancer Discov. 2011 Nov;1(6):481-6
22348200
Genes Dev. 2012 Jul 15;26(14):1573-86
22802530
Nat Commun. 2015 Oct 07;6:8501
26442967
Oncogene. 2016 Jul 7;35(27):3607-12
26500061
Nat Med. 2007 Oct;13(10 ):1203-10
17873882
Nat Rev Neurosci. 2009 Dec;10(12):850-60
19927149
Oncogene. 2000 Mar 23;19(13):1684-90
10763825
J Immunol. 1996 Oct 1;157(7):2864-72
8816391
Leukemia. 2005 Nov;19(11):1948-57
16107895
Nat Genet. 2013 Oct;45(10):1141-9
23917401
J Biol Chem. 2007 May 11;282(19):14379-88
17374610
Leukemia. 2000 Oct;14(10):1766-76
11021752
Blood. 2008 Dec 15;112(13):5095-102
18824601
J Clin Invest. 2005 Mar;115(3):653-63
15765148
Nature. 2012 Apr 15;485(7397):260-3
22504184
J Biol Chem. 1997 Nov 28;272(48):30334-9
9374521
PLoS One. 2013 Jul 09;8(7):e67990
23874483
Leukemia. 2009 Nov;23(11):2102-8
19626047
Cancer Cell. 2012 Apr 17;21(4):459-72
22516257
Nature. 2007 Jun 21;447(7147):966-71
17515920
Blood. 2011 Jan 13;117(2):591-4
20959606
Nat Genet. 2014 May;46(5):444-50
24705251
Blood. 2005 Jul 1;106(1):274-86
15774621
Oncogene. 2015 Jul;34(27):3593-604
25241901
Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):10299-304
24982195
Nature. 2004 Aug 26;430(7003):1034-9
15329723
Cell. 1991 Apr 5;65(1):189-97
1849459
Nature. 1991 Mar 14;350(6314):158-60
1706478