Notch signaling contributes to proliferation and tumor formation of human T-cell leukemia virus type 1-associated adult T-cell leukemia.
The Notch signaling pathway plays an important role in cellular proliferation, differentiation, and apoptosis. Unregulated activation of Notch signaling can result in excessive cellular proliferation and cancer. Human T-cell leukemia virus type 1 (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL). The disease has a dismal prognosis and is invariably fatal. In this study, we report a high frequency of constitutively activated Notch in ATL patients. We found activating mutations in Notch in more than 30% of ATL patients. These activating mutations are phenotypically different from those previously reported in T-ALL leukemias and may represent polymorphisms for activated Notch in human cancers. Compared with the exclusive activating frameshift mutations in the proline, glutamic acid, serine, and threonine (PEST) domain in T-ALLs, those in ATLs have, in addition, single-substitution mutations in this domain leading to reduced CDC4/Fbw7-mediated degradation and stabilization of the intracellular cleaved form of Notch1 (ICN1). Finally, we demonstrated that inhibition of Notch signaling by γ-secretase inhibitors reduced tumor cell proliferation and tumor formation in ATL-engrafted mice. These data suggest that activated Notch may be important to ATL pathogenesis and reveal Notch1 as a target for therapeutic intervention in ATL patients.
Pancewicz
Joanna
J
Department of Pathology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Taylor
John M
JM
Datta
Abhik
A
Baydoun
Hicham H
HH
Waldmann
Thomas A
TA
Hermine
Olivier
O
Nicot
Christophe
C
D000328:Adult; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004252:DNA Mutational Analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D044767:Ubiquitin-Protein Ligases; D053829:Amyloid Precursor Protein Secretases
Science. 2004 Oct 8;306(5694):269-71
15472075
Science. 1995 Jul 7;269(5220):79-81
7604283
Clin Cancer Res. 2006 May 15;12(10):3043-9
16707600
Nat Med. 2009 Jan;15(1):50-8
19098907
J Exp Med. 2007 Aug 6;204(8):1813-24
17646409
Blood. 2004 Sep 15;104(6):1696-702
15187027
Nat Med. 2004 Feb;10(2):197-201
14730358
Proc Natl Acad Sci U S A. 1984 Apr;81(8):2534-7
6326131
Blood. 2006 Aug 15;108(4):1151-7
16614245
Blood. 2008 Feb 15;111(4):2220-9
18039953
J Biol Chem. 2001 Sep 14;276(37):34371-8
11425854
Nat Rev Immunol. 2008 May;8(5):380-90
18421304
Nature. 1995 Sep 28;377(6547):355-8
7566092
Int J Cancer. 2007 Nov 15;121(10):2205-11
17657714
Nat Rev Cancer. 2006 May;6(5):347-59
16612405
Cell Cycle. 2005 Oct;4(10):1356-9
16131838
Oncogene. 2008 Sep 1;27(38):5148-67
18758484
Oncogene. 2007 Oct 15;26(47):6838-49
17934490
J Exp Med. 1985 Dec 1;162(6):2169-74
2866223
Blood. 2007 Jul 1;110(1):278-86
17363738
Proc Natl Acad Sci U S A. 1980 Dec;77(12):7415-9
6261256
Nat Rev Cancer. 2008 Feb;8(2):83-93
18094723
Oncogene. 2005 Sep 22;24(42):6333-44
15940249
Science. 1999 Apr 30;284(5415):770-6
10221902
J Clin Oncol. 2009 Jan 20;27(3):453-9
19064971
Blood. 2009 Jun 11;113(24):6172-81
19246562
Cancer Biol Ther. 2002 Jul-Aug;1(4):337-41
12432242
Mol Cell Biol. 2004 Nov;24(21):9265-73
15485896
J Clin Invest. 2008 Sep;118(9):3181-94
18677410
Nat Med. 2007 Oct;13(10):1203-10
17873882
Nat Genet. 2000 Dec;26(4):484-9
11101851