AUTHOR=Hong Chang-Sook , Muller Laurent , Whiteside Theresa L. , Boyiadzis Michael 

TITLE=Plasma Exosomes as Markers of Therapeutic Response in Patients with Acute Myeloid Leukemia

JOURNAL=Frontiers in Immunology

VOLUME=5

YEAR=2014

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00160

DOI=10.3389/fimmu.2014.00160

ISSN=1664-3224

ABSTRACT=<p><bold>Purpose:</bold> Exosomes isolated from the plasma of newly diagnosed acute myeloid leukemia (AML) patients have elevated protein and transforming growth factor-beta 1 (TGF-β1) contents and inhibit natural killer (NK) cell cytotoxicity (<italic>Haematologica</italic> 96, p. 1302, 2011). A potential role of exosomes in predicting responses to chemotherapy (CT) was evaluated in AML patients undergoing treatment.</p><p><bold>Experimental Design:</bold> Plasma was obtained from AML patients at diagnosis (<italic>n</italic> = 16); post-induction CT (<italic>n</italic> = 9); during consolidation CT (<italic>n</italic> = 10); in long-term remission (Lt-CR, <italic>n</italic> = 5); and from healthy volunteers (<italic>n</italic> = 7). Exosomes were isolated by size-exclusion chromatography and ultracentrifugation. The exosomal protein, soluble TGFβ-1 levels (ELISA), and the TGF-β1 profiles (western blots) were compared among patients’ cohorts. The results were correlated with the patients’ cytogenetic profile, percentage of leukemic blast, and outcome.</p><p><bold>Results:</bold> At diagnosis, protein and TGF-β1 levels were higher (<italic>p</italic> &lt; 0.009 and <italic>p</italic> &lt; 0.004) in AML than control exosomes. These values decreased after induction CT (<italic>p</italic> &lt; 0.05 and <italic>p</italic> &lt; 0.004), increased during consolidation CT (<italic>p</italic> &lt; 0.02 and <italic>p</italic> &lt; 0.005), and normalized in Lt-CR. While TGF-β1 and protein levels tracked one another, TGF-β1 pro-peptide, latency-associated peptide (LAP), or mature TGF-β1 differentially decorated exosomes isolated before, during, and after CT. Only TGF-β1 pro-peptide was seen in exosomes of controls or Lt-CR patients. During consolidation CT, exosomes carried TGF-β1 pro-peptide, LAP, and low levels of mature TGF-β1. NK cell co-incubation with AML exosomes carrying all three TGF-β1 forms induced down-regulation of NKG2D expression.</p><p><bold>Conclusion:</bold> Changes in exosomal protein and/or TGF-β1 content may reflect responses to CT. The exosomal profile may suggest the presence of residual disease in patients considered to have achieved complete remission.</p>