Abstract
BackgroundIncreased plasma levels of proteasome have been associated with various neoplasms, especially myeloid malignancies. Little is known of the cellular origin and release mechanisms of such proteasome. We recently identified and characterized a novel particulate cytoplasmic structure (PaCS) showing selective accumulation of ubiquitin-proteasome system (UPS) components. PaCSs have been reported in some epithelial neoplasms and in two genetic disorders characterized by hematopoietic cell dysplasia and increased risk of leukemia. However, no information is available about PaCSs in hematopoietic neoplasms.MethodsPaCSs were investigated by ultrastructural, immunogold, and immunofluorescence analysis of bone marrow (BM) biopsies and peripheral blood (PB) cell preparations of 33 consecutive, untreated, or relapsed patients affected by different hematopoietic neoplasms. BM and PB samples from individuals with non-neoplastic BM or healthy donors were studied as controls. Granulocytes and platelet proteasome content was measured by immunoblotting and plasma proteasome levels by ELISA.ResultsPaCSs with typical, selective immunoreactivity for polyubiquitinated proteins and proteasome were widespread in granulocytic cells, megakaryocytes, and platelets of patients with myeloproliferative neoplasms (MPN). In acute myeloid leukemia and myelodysplastic syndromes (MDS), PaCSs were only occasionally detected in blast cells and were found consistently in cells showing granulocytic and megakaryocytic maturation. Conversely, PaCSs were poorly represented or absent in non-neoplastic hematopoietic tissue or lymphoid neoplasms. In MPN granulocytes and platelets, the presence of PaCSs was associated with increased amounts of proteasome in cell lysates. PaCSs were often localized in cytoplasmic blebs generating PaCSs-filled plasma membrane vesicles observable in the BM intercellular space. In MPN and MDS, accumulation of PaCSs was associated with significant increase in plasma proteasome. Immunogold analysis showed that PaCSs of myeloid neoplasia selectively concentrated the chaperone proteins Hsp40, Hsp70, and Hsp90. ConclusionsPaCSs accumulate in cells of myeloid neoplasms in a lineage- and maturation-restricted manner; in particular, they are widespread in granulocytic and megakaryocytic lineages of MPN patients. PaCSs development was associated with excess accumulation of polyubiquitinated proteins, proteasome, and chaperone molecules, indicating impairment of the UPS-dependent protein homeostasis and a possible link with Hsp90-related leukemogenesis. A mechanism of PaCSs discharge by leukemic cells could contribute to increased plasma proteasome of MPN and MDS.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0169-6) contains supplementary material, which is available to authorized users.
Highlights
Increased plasma levels of proteasome have been associated with various neoplasms, especially myeloid malignancies
particulate cytoplasmic structure (PaCS) in hematological neoplasms Combined ultrastructural and immunogold analysis showed that PaCSs were extensive in bone marrow (BM) of patients with myeloproliferative neoplasms (MPN), including chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)
In the cases of PMF and ET, we occasionally observed PaCSs in BM stromal cells, including fibroblasts, which were increased in the presence of BM fibrosis (Fig. 2c)
Summary
Increased plasma levels of proteasome have been associated with various neoplasms, especially myeloid malignancies. Increased cellular expression and activity of proteasome have been reported in a variety of neoplasms, including hematological, epithelial, and neurological tumors [1,2,3,4,5] This has led to the proposal of proteasome inhibitors as antineoplastic therapy, with clinically relevant results in some tumors, such as plasma cell myeloma and mantle cell lymphoma [6, 7]. Both epithelial and hemopoietic neoplasms have been associated with increased plasma levels of proteasome which were disease type, stage, and therapy sensitive [8,9,10,11]. Limited information is available on the fate of such proteins and whether they are totally degraded inside neoplastic cells or at least in part discharged extracellularly together with proteasome components
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