Phospho-flow detection of constitutive and cytokine-induced pSTAT3/5, pAKT and pERK expression highlights novel prognostic biomarkers for patients with multiple myeloma

被引:18
作者
Brown, R. [1 ]
Yang, S. [1 ]
Weatherburn, C. [1 ]
Gibson, J. [1 ]
Ho, P. J. [1 ]
Suen, H. [1 ]
Hart, D. [2 ]
Joshua, D. [1 ]
机构
[1] Royal Prince Alfred Hosp, Inst Haematol, Sydney, NSW 2050, Australia
[2] ANZAC Res Inst, Sydney, NSW, Australia
关键词
SIGNAL TRANSDUCER; POOR-PROGNOSIS; ACTIVATION; STAT3; CELLS; APOPTOSIS; PATHWAY; PROTEIN; CANCER; INFLAMMATION;
D O I
10.1038/leu.2014.204
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Identifying check points in cell signal transduction pathways has led to the development of new cancer therapies; however, relatively few studies have determined the diagnostic and prognostic significance of analysing phosphorylated signaling proteins in patient blood and bone marrow (BM) samples. This is the first comprehensive phospho-flow study of both constitutive and cytokine-induced pSTAT3, pSTAT5, pAKT and phosphorylated extracellular signal-regulated kinase (pERK) expression in malignant plasma cells of patients with monoclonal gammopathies. In diagnostic BM samples from 65 patients with multiple myeloma (MM), interleukin (IL)-6-induced pSTAT3 proved to be a new and independent prognostic biomarker for improved survival. When combined with the International Staging System, 6 subgroups demonstrated stratified median survivals from 9 to 72 months (chi(2) = 34.3; P < 0.0001). In contrast, constitutive expression of pSTAT3, pSTAT5, pAKT and pERK did not assist the differential diagnosis nor determine prognosis. High pSTAT3 expression was dependent on existing CD45 expression and pSTAT5 appeared to regulate IgG production. Phospho-flow cytometry could be used to screen for personalized therapy, although the lack of clinical significance of constitutive pSTAT3 levels suggests that pSTAT3 blockade may not be clinically relevant in MM. This study has revealed novel prognostic biomarkers and insights into the biology of signaling pathways in patients with MM.
引用
收藏
页码:483 / 490
页数:8
相关论文
共 37 条
[1]   The Incidence, Correlation with Tumor-Infiltrating Inflammation, and Prognosis of Phosphorylated STAT3 Expression in Human Gliomas [J].
Abou-Ghazal, Mohamed ;
Yang, David S. ;
Qiao, Wei ;
Reina-Ortiz, Chantal ;
Wei, Jun ;
Kong, Ling-Yuan ;
Fuller, Gregory N. ;
Hiraoka, Nobuyoshi ;
Priebe, Waldemar ;
Sawaya, Raymond ;
Heimberger, Amy B. .
CLINICAL CANCER RESEARCH, 2008, 14 (24) :8228-8235
[2]   Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival [J].
Benekli, M ;
Xia, Z ;
Donohue, KA ;
Ford, LA ;
Pixley, LA ;
Baer, MR ;
Baumann, H ;
Wetzler, M .
BLOOD, 2002, 99 (01) :252-257
[3]   Nuclear factor-κB and STAT3 are constitutively active in CD138+ cells derived from multiple myeloma patients, and suppression of these transcription factors leads to apoptosis [J].
Bharti, AC ;
Shishodia, S ;
Reuben, JM ;
Weber, D ;
Alexanian, R ;
Raj-Vadhan, S ;
Estrov, Z ;
Talpaz, M ;
Aggarwal, BB .
BLOOD, 2004, 103 (08) :3175-3184
[4]   Interleukin-21 is a growth and survival factor for human myeloma cells [J].
Brenne, AT ;
Ro, TB ;
Waage, A ;
Sundan, A ;
Borset, M ;
Hjorth-Hansen, H .
BLOOD, 2002, 99 (10) :3756-3762
[5]   STAT proteins:: From normal control of cellular events to tumorigenesis [J].
Calò, V ;
Migliavacca, M ;
Bazan, V ;
Macaluso, M ;
Buscemi, M ;
Gebbia, N ;
Russo, A .
JOURNAL OF CELLULAR PHYSIOLOGY, 2003, 197 (02) :157-168
[6]   Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells [J].
Catlett-Falcone, R ;
Landowski, TH ;
Oshiro, MM ;
Turkson, J ;
Levitzki, A ;
Savino, R ;
Ciliberto, G ;
Moscinski, L ;
Fernández-Luna, JL ;
Nuñez, G ;
Dalton, WS ;
Jove, R .
IMMUNITY, 1999, 10 (01) :105-115
[7]   STATs and gene regulation [J].
Darnell, JE .
SCIENCE, 1997, 277 (5332) :1630-1635
[8]   Activation of the IL-6R/Jak/Stat Pathway is Associated with a Poor Outcome in Resected Pancreatic Ductal Adenocarcinoma [J].
Denley, Simon M. ;
Jamieson, Nigel B. ;
McCall, Pamela ;
Oien, Karin A. ;
Morton, Jennifer P. ;
Carter, C. Ross ;
Edwards, Joanne ;
McKay, Colin J. .
JOURNAL OF GASTROINTESTINAL SURGERY, 2013, 17 (05) :887-898
[9]   Targeting ras signalling pathways in cancer therapy [J].
Downward, J .
NATURE REVIEWS CANCER, 2003, 3 (01) :11-22
[10]  
Fabbro D, 2012, METHODS MOL BIOL, V795, P1, DOI 10.1007/978-1-61779-337-0_1