Τίτλος:
The Stat3/5 signaling biosignature in hematopoietic stem/progenitor cells predicts response and outcome in myelodysplastic syndrome patients treated with azacitidine
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Purpose: Azacitidine is the mainstay of high-risk myelodysplastic syndromes (MDS) therapy, but molecular predictors of response and the mechanisms of resistance to azacitidine remain largely unidentified. Deregulation of signaling via Stat3 and Stat5 in acute myeloid leukemia (AML) is associated with aggressive disease. Numerous genes involved in cell signaling are aberrantly methylated inMDS, yet the alterations and the effect of azacitidine treatment on Stat3/5 signaling in high-risk MDS have not been explored. Experimental Design: We assessed longitudinally constitutive and ligand-induced phospho-Stat3/5 signaling responses by multiparametric flow cytometry in 74 patients with MDS and low blast count AML undergoing azacitidine therapy. Pretreatment Stat3/5 signaling profiles in CD34+ cells were grouped by unsupervised clustering. The differentiation stage and the molecular properties of the CD34+ G-CSF-inducible Stat3/5 double-positive subpopulation were performed by flow cytometry and quantitative real-time PCR in isolated MDS progenitors. Results: The pretreatment Stat3/5 signaling profiles in CD34+ cells correlated strongly with response and cytogenetics and independently predicted event-free survival. We further identified a CD34+ G-CSF-inducible Stat3/5 double-positive subpopulation (DP subset) whose pretreatment levels were inversely associated with treatment response and cytogenetics. The kinetics of the DP subset followed the response to azacitidine and the disease course, whereas its molecular characteristics and cellular hierarchy were consistent with a leukemia propagating cell phenotype. Conclusions: Our findings provide a novel link among Stat3/5 signaling and MDS pathobiology and suggest that the Stat3/5 signaling biosignature may serve as both a response biomarker and treatment target. © 2015 AACR.
Συγγραφείς:
Miltiades, P.
Lamprianidou, E.
Vassilakopoulos, T.P.
Papageorgiou, S.G.
Galanopoulos, A.G.
Kontos, C.K.
Adamopoulos, P.G.
Nakou, E.
Vakalopoulou, S.
Garypidou, V.
Papaioannou, M.
Hatjiharissi, E.
Papadaki, H.A.
Spanoudakis, E.
Pappa, V.
Scorilas, A.
Tsatalas, C.
Kotsianidis, I.
on behalf of the Hellenic MDS Study Group
Περιοδικό:
Clinical Cancer Research
Εκδότης:
American Association for Cancer Research Inc.
Λέξεις-κλειδιά:
azacitidine; CD34 antigen; granulocyte colony stimulating factor; STAT3 protein; STAT5 protein; antineoplastic antimetabolite; azacitidine; biological marker; granulocyte colony stimulating factor; proteome; STAT3 protein; STAT5 protein, adult; aged; Article; carcinogenesis; controlled study; cytogenetics; disease course; drug dose reduction; event free survival; female; hematopoietic stem cell; human; human cell; longitudinal study; lymphocyte differentiation; major clinical study; male; multiple cycle treatment; myelodysplastic syndrome; phenotype; prediction; priority journal; protein protein interaction; signal transduction; T lymphocyte subpopulation; treatment outcome; treatment response; cancer stem cell; cluster analysis; drug effects; hematopoietic stem cell; immunophenotyping; Leukemia, Myeloid, Acute; metabolism; middle aged; mortality; Myelodysplastic Syndromes; pathology; prognosis; survival analysis; very elderly, Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Azacitidine; Biomarkers; Cluster Analysis; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Immunophenotyping; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Neoplastic Stem Cells; Phenotype; Prognosis; Proteome; Signal Transduction; STAT3 Transcription Factor; STAT5 Transcription Factor; Survival Analysis; Treatment Outcome
DOI:
10.1158/1078-0432.CCR-15-1288
