Elevated VMP1 expression in acute myeloid leukemia amplifies autophagy and is protective against venetoclax-induced apoptosis
| Autor: | Jan Jacob Schuringa, Edo Vellenga, Fiona A.J. van den Heuvel, Jennifer Jaques, Roy R Woldhuis, Darlyne S Kluit, Hendrik Folkerts, Albertus T. J. Wierenga |
|---|---|
| Přispěvatelé: | Stem Cell Aging Leukemia and Lymphoma (SALL), Guided Treatment in Optimal Selected Cancer Patients (GUTS) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Myeloid Immunology CD34 Antigens CD34 Antineoplastic Agents Apoptosis Mice Transgenic Article Acute myeloid leukaemia Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Sequestosome-1 Protein Autophagy medicine Animals Humans RNA Small Interfering lcsh:QH573-671 Progenitor cell Sulfonamides lcsh:Cytology Chemistry Mitophagy Membrane Proteins Myeloid leukemia Cell Cycle Checkpoints Mitochondrial Turnover Cell Biology Bridged Bicyclo Compounds Heterocyclic Fetal Blood medicine.disease Mitochondria Cell biology Leukemia Myeloid Acute Leukemia Haematopoiesis 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Leukocytes Mononuclear Female RNA Interference |
| Zdroj: | Cell death & disease, 10(6):421. Nature Publishing Group Cell Death and Disease, Vol 10, Iss 6, Pp 1-12 (2019) Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | Vacuole membrane protein (VMP1) is a putative autophagy protein, which together with Beclin-1 acts as a molecular switch in activating autophagy. In the present study the role of VMP1 was analysed in CD34+ cells of cord blood (CB) and primary acute myeloid leukemia (AML) cells and cell lines. An increased expression of VMP1 was observed in a subset of AML patients. Functional studies in normal CB CD34+ cells indicated that inhibiting VMP1 expression reduced autophagic-flux, coinciding with reduced expansion of hematopoietic stem and progenitor cells (HSPC), delayed differentiation, increased apoptosis and impaired in vivo engraftment. Comparable results were observed in leukemic cell lines and primary AML CD34+ cells. Ultrastructural analysis indicated that leukemic cells overexpressing VMP1 displayed a reduced number of mitochondrial structures, while the number of lysosomal degradation structures was increased. The overexpression of VMP1 did not affect cell proliferation and differentiation, but increased autophagic-flux and improved mitochondrial quality, which coincided with an increased threshold for venetoclax-induced loss of mitochondrial outer membrane permeabilization (MOMP) and apoptosis. In conclusion, our data indicate that in leukemic cells high VMP1 is involved with mitochondrial quality control. |
| Databáze: | OpenAIRE |
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