Abstract
Purpose: 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 (Haematologica 96, p. 1302, 2011). A potential role of exosomes in predicting responses to chemotherapy (CT) was evaluated in AML patients undergoing treatment.Experimental Design: Plasma was obtained from AML patients at diagnosis (n = 16); post-induction CT (n = 9); during consolidation CT (n = 10); in long-term remission (Lt-CR, n = 5); and from healthy volunteers (n = 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.Results: At diagnosis, protein and TGF-β1 levels were higher (p < 0.009 and p < 0.004) in AML than control exosomes. These values decreased after induction CT (p < 0.05 and p < 0.004), increased during consolidation CT (p < 0.02 and p < 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.Conclusion: 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.
Highlights
Sixty to eighty percent of adult patients with newly diagnosed acute myeloid leukemia (AML) attain a complete remission (CR) with intensive induction chemotherapy [CT; Ref. [1, 2]]
TGF-β1 pro-peptide was seen in exosomes of controls or Lt-CR patients
We report here that changes in total exosomal protein levels and the presence of different forms of transforming growth factor-beta 1 (TGF-β1) carried by AML exosomes reflect effects of therapy and might serve as indicators of leukemic relapse in AML patients
Summary
Sixty to eighty percent of adult patients with newly diagnosed acute myeloid leukemia (AML) attain a complete remission (CR) with intensive induction chemotherapy [CT; Ref. [1, 2]]. Sixty to eighty percent of adult patients with newly diagnosed acute myeloid leukemia (AML) attain a complete remission (CR) with intensive induction chemotherapy [CT; Ref. Post-remission therapy aims to destroy leukemia cells that survive induction CT but are undetectable by conventional methods. Exosomes are virus-size (30–100 nm in diameter) membranebound microvesicles that are formed within the endocytic compartments and via fusion of multivesicles bodies with the cell membrane are released into the extracellular space [3]. The exosome fractions obtained from plasma of cancer patients are enriched in various immunosuppressive molecules and in proteins/glycoproteins expressed on cell membranes and/or in the cytosol of the parent tumor cells. In AML, we reported highly elevated exosome plasma levels in newly diagnosed untreated AML patients compared to the levels measured in normal controls [NC; Ref. In AML, we reported highly elevated exosome plasma levels in newly diagnosed untreated AML patients compared to the levels measured in normal controls [NC; Ref. [4]]
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