Acute myeloid leukemia

DPP4+ exosomes in AML patients’ plasma suppress proliferation of hematopoietic progenitor cells

Abstract

Mechanisms by which acute myeloid leukemia (AML) interferes with normal hematopoiesis are under intense investigation. Emerging evidence suggests that exosomes produced by leukemia blasts suppress hematopoiesis. Exosomes isolated from AML patients’ plasma at diagnosis significantly and dose-dependently suppressed colony formation of normal hematopoietic progenitor cells (HPC). Levels of HPC suppression mediated by exosomes of AML patients who achieved complete remission (CR) were significantly decreased compared to those observed at AML diagnosis. Exosomes from plasma of patients who had achieved CR but with incomplete cell count recovery (CRi) after chemotherapy suppressed in vitro colony formation as effectively as did exosomes obtained at AML diagnosis. Dipeptidylpeptidase4 (DPP4/CD26), a serine protease that cleaves select penultimate amino acids of various proteins, has been previously implicated in the regulation of hematopoiesis. DPP4 was carried by exosomes from AML plasma or leukemia cell lines. Leukemia exosomes which suppressed HSC colony formation had markedly higher DPP4 functional activity than that detected in the exosomes of normal donors. Pharmacological inhibition of DPP4 activity in AML exosomes reversed the effects of exosome-mediated myelosuppression. Reversing the negative effects of exosomes on AML hematopoiesis, and thus improving cell count recovery, might emerge as a new therapeutic approach to AML.

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Fig. 1: Characteristics and molecular profile of isolated exosomes.
Fig. 2: DPP4 in leukemia exosomes is enzymatically active.
Fig. 3: Effects of leukemia exosomes on the proliferation of normal hematopoietic progenitor cells.
Fig. 4: Effects of leukemia exosomes from patients in complete remission.

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Funding

This work was supported by the U.S National Cancer Institute grant R21 CA205644 to TLW and MB and by NIH R35 HL139599 to HB.

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Correspondence to Michael Boyiadzis.

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Namburi, S., Broxmeyer, H.E., Hong, CS. et al. DPP4+ exosomes in AML patients’ plasma suppress proliferation of hematopoietic progenitor cells. Leukemia (2020). https://doi.org/10.1038/s41375-020-01047-7

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