Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia.
PTPN2 (protein tyrosine phosphatase non-receptor type 2, also known as TC-PTP) is a cytosolic tyrosine phosphatase that functions as a negative regulator of a variety of tyrosine kinases and other signaling proteins. In agreement with its role in the regulation of the immune system, PTPN2 was identified as a susceptibility locus for autoimmune diseases. In this work, we describe the identification of focal deletions of PTPN2 in human T-cell acute lymphoblastic leukemia (T-ALL). Deletion of PTPN2 was specifically found in T-ALLs with aberrant expression of the TLX1 transcription factor oncogene, including four cases also expressing the NUP214-ABL1 tyrosine kinase. Knockdown of PTPN2 increased the proliferation and cytokine sensitivity of T-ALL cells. In addition, PTPN2 was identified as a negative regulator of NUP214-ABL1 kinase activity. Our study provides genetic and functional evidence for a tumor suppressor role of PTPN2 and suggests that expression of PTPN2 may modulate response to treatment.
Kleppe
Maria
M
Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium.
Lahortiga
Idoya
I
El Chaar
Tiama
T
De Keersmaecker
Kim
K
Mentens
Nicole
N
Graux
Carlos
C
Van Roosbroeck
Katrien
K
Ferrando
Adolfo A
AA
Langerak
Anton W
AW
Meijerink
Jules P P
JP
Sigaux
François
F
Haferlach
Torsten
T
Wlodarska
Iwona
I
Vandenberghe
Peter
P
Soulier
Jean
J
Cools
Jan
J
D000818:Animals; D001549:Benzamides; D002460:Cell Line; D045744:Cell Line, Tumor; D054402:Chemokine CCL1 / Q000378:metabolism; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D007376:Interleukin-2 / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism; D007942:Leukemia, Experimental / Q000235:genetics; D051379:Mice; D010879:Piperazines / Q000627:therapeutic use; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use
D001549:Benzamides; D054402:Chemokine CCL1; D018398:Homeodomain Proteins; D007376:Interleukin-2; D015851:Interleukin-7; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; C071250:TLX1 protein, human; D000068877:Imatinib Mesylate; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2
Haematologica. 2008 Apr;93(4):533-42
18322257
Nat Rev Cancer. 2006 May;6(5):347-59
16612405
J Exp Med. 2008 Apr 14;205(4):751-8
18362173
Cancer Cell. 2002 Feb;1(1):75-87
12086890
Nat Genet. 2004 Oct;36(10):1084-9
15361874
Nature. 2007 Jun 7;447(7145):661-78
17554300
Mol Cell. 2008 Jul 11;31(1):134-42
18614052
Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):499-503
1731319
Haematologica. 2005 Aug;90(8):1116-27
16079112
Nat Genet. 2007 Jul;39(7):857-64
17554260
Mol Cell Biol. 2002 Aug;22(16):5662-8
12138178
Curr Biol. 2002 Mar 19;12(6):446-53
11909529
J Cell Biol. 1995 Nov;131(3):631-43
7593185
Blood. 2007 Aug 15;110(4):1251-61
17452517
J Exp Med. 2005 Jun 6;201(11):1715-23
15928199
Nat Genet. 2007 May;39(5):593-5
17435759
Nature. 2008 May 1;453(7191):110-4
18408710
Immunol Rev. 2009 Mar;228(1):325-41
19290937
Leukemia. 1995 Oct;9(10):1783-6
7564526
Blood. 2005 Jun 15;105(12):4849-52
15713800
Mol Cell Biol. 1994 Apr;14(4):2429-37
8139546
Methods. 2005 Jan;35(1):44-53
15588985
Mol Cell Biol. 2007 Mar;27(6):2166-79
17210636
J Biol Chem. 1997 Aug 22;272(34):21548-57
9261175
Nat Immunol. 2005 Mar;6(3):253-60
15696169
Cancer Cell. 2008 Aug 12;14(2):166-79
18691551
Blood. 2005 Jul 1;106(1):274-86
15774621
Nat Rev Immunol. 2008 May;8(5):380-90
18421304
Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1680-5
9050838
Nat Rev Immunol. 2001 Dec;1(3):200-8
11905829