Functional impact of NOTCH1 mutations in chronic lymphocytic leukemia

被引:92
作者
Arruga, F. [1 ]
Gizdic, B. [1 ,2 ]
Serra, S. [1 ,3 ]
Vaisitti, T. [1 ]
Ciardullo, C. [4 ]
Coscia, M. [5 ]
Laurenti, L. [6 ]
D'Arena, G. [7 ]
Jaksic, O. [2 ]
Inghirami, G. [8 ]
Rossi, D. [4 ]
Gaidano, G. [4 ]
Deaglio, S. [1 ,3 ]
机构
[1] Univ Turin, Sch Med, Dept Med Sci, I-10126 Turin, Italy
[2] Dubrava Univ Hosp, Dept Hematol, Zagreb, Croatia
[3] Human Genet Fdn HuGeF, I-10126 Turin, Italy
[4] Amedeo Avogadro Univ Eastern Piedmont, Div Hematol, Dept Translat Med, Novara, Italy
[5] Citta Salute & Sci Univ Hosp, Ctr Expt Res & Med Studies, Lab Hematol Oncol, Div Hematol, Turin, Italy
[6] Univ Cattolica Sacro Cuore, Inst Hematol, I-00168 Rome, Italy
[7] Ctr Riferimento Oncol Basilicata, IRCCS, Dept Oncohematol, Rionero In Vulture, Italy
[8] Univ Turin, Ctr Expt Res & Med Studies, Dept Mol Biotechnol & Hlth Sci, I-10126 Turin, Italy
关键词
chronic lymphocytic leukemia; NOTCH1; mutations; micro-environment; ACUTE LYMPHOBLASTIC-LEUKEMIA; SIGNALING PATHWAY; GENOMIC ABERRATIONS; CLL CELLS; CD38; EXPRESSION; SURVIVAL; CANCER; ACTIVATION; RESISTANCE;
D O I
10.1038/leu.2013.319
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The purpose of this study was to compare the expression and function of NOTCH1 in chronic lymphocytic leukemia (CLL) patients harboring a wild-type (WT) or mutated NOTCH1 gene. NOTCH1 mRNA and surface protein expression levels were independent of the NOTCH1 gene mutational status, consistent with the requirement for NOTCH1 signaling in this leukemia. However, compared with NOTCH1-WT CLL, mutated cases displayed biochemical and transcriptional evidence of an intense activation of the NOTCH1 pathway. In vivo, expression and activation of NOTCH1 was highest in CLL cells from the lymph nodes as confirmed by immunohistochemistry. In vitro, the NOTCH1 pathway was rapidly downregulated, suggesting that signaling relies upon microenvironmental interactions even in NOTCH1-mutated cases. Accordingly, co-culture of Jagged1 (the NOTCH1 ligand) nurse-like cells with autologous CLL cells sustained NOTCH1 activity over time and mediated CLL survival and resistance against pro-apoptotic stimuli, both abrogated when NOTCH1 signaling was pharmacologically switched off. Together, these results show that NOTCH1 mutations have stabilizing effects on the NOTCH1 pathway in CLL. Furthermore, micro-environmental interactions appear critical in activating the NOTCH1 pathway both in WT and mutated patients. Finally, NOTCH1 signals may create conditions that favor drug resistance, thus making NOTCH1 a potential molecular target in CLL.
引用
收藏
页码:1060 / 1070
页数:11
相关论文
共 54 条
[1]   Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts [J].
Agnusdei, V. ;
Minuzzo, S. ;
Frasson, C. ;
Grassi, A. ;
Axelrod, F. ;
Satyal, S. ;
Gurney, A. ;
Hoey, T. ;
Seganfreddo, E. ;
Basso, G. ;
Valtorta, S. ;
Moresco, R. M. ;
Amadori, A. ;
Indraccolo, S. .
LEUKEMIA, 2014, 28 (02) :278-288
[2]   NOTCH1 mutations in CLL associated with trisomy 12 [J].
Balatti, Veronica ;
Bottoni, Arianna ;
Palamarchuk, Alexey ;
Alder, Hansjuerg ;
Rassenti, Laura Z. ;
Kipps, Thomas J. ;
Pekarsky, Yuri ;
Croce, Carlo M. .
BLOOD, 2012, 119 (02) :329-331
[3]   A novel proteolytic cleavage involved in Notch signaling:: The role of the disintegrin-metalloprotease TACE [J].
Brou, C ;
Logeat, F ;
Gupta, N ;
Bessia, C ;
LeBail, O ;
Doedens, JR ;
Cumano, A ;
Roux, P ;
Black, RA ;
Israël, A .
MOLECULAR CELL, 2000, 5 (02) :207-216
[4]  
Burger JA, 2000, BLOOD, V96, P2655
[5]   Dynamic binding of RBPJ is determined by Notch signaling status [J].
Castel, David ;
Mourikis, Philippos ;
Bartels, Stefanie J. J. ;
Brinkman, Arie B. ;
Tajbakhsh, Shahragim ;
Stunnenberg, Hendrik G. .
GENES & DEVELOPMENT, 2013, 27 (09) :1059-1071
[6]   Making sense of cancer genomic data [J].
Chin, Lynda ;
Hahn, William C. ;
Getz, Gad ;
Meyerson, Matthew .
GENES & DEVELOPMENT, 2011, 25 (06) :534-555
[7]   Mechanisms of disease: Chronic lymphocytic leukemia [J].
Chiorazzi, N ;
Rai, KR ;
Ferrarini, M .
NEW ENGLAND JOURNAL OF MEDICINE, 2005, 352 (08) :804-815
[8]   ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia [J].
Crespo, M ;
Bosch, F ;
Villamor, N ;
Bellosillo, B ;
Colomer, D ;
Rozman, M ;
Marcé, S ;
López-Guillermo, A ;
Campo, E ;
Montserrat, E .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 348 (18) :1764-1775
[9]   Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia [J].
Damle, RN ;
Wasil, T ;
Fais, F ;
Ghiotto, F ;
Valetto, A ;
Allen, SL ;
Buchbinder, A ;
Budman, D ;
Dittmar, K ;
Kolitz, J ;
Lichtman, SM ;
Schulman, P ;
Vinciguerra, VP ;
Rai, KR ;
Ferrarini, M ;
Chiorazzi, N .
BLOOD, 1999, 94 (06) :1840-1847
[10]   Vertebrate hairy and Enhancer of split related proteins: transcriptional repressors regulating cellular differentiation and embryonic patterning [J].
Davis, RL ;
Turner, DL .
ONCOGENE, 2001, 20 (58) :8342-8357