title: Phospho-flow detection of constitutive and cytokine-induced pSTAT3/5, pAKT and pERK expression highlights novel prognostic biomarkers for patients with multiple myeloma.
abstract: 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 (χ(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.
authors.affiliation: Institute of Haematology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Brown
authors.affiliation: Institute of Haematology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Yang
authors.affiliation: Institute of Haematology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Weatherburn
authors.affiliation: Institute of Haematology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Gibson
authors.affiliation: Institute of Haematology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: P J
authors.initials: PJ
authors.lastname: Ho
authors.affiliation: Institute of Haematology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Suen
authors.affiliation: Dendritic Cell Biology and Therapeutics, ANZAC Research Institute, Sydney, NSW, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Hart
authors.affiliation: Institute of Haematology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Joshua
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002470:Cell Survival; D015331:Cohort Studies; D015925:Cryopreservation; D016207:Cytokines / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood* / Q000175:diagnosis / Q000276:immunology*; D010766:Phosphorylation; D011379:Prognosis; D019947:Receptors, Interleukin-6 / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; D016207:Cytokines; D007074:Immunoglobulin G; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D017493:Leukocyte Common Antigens