Consequences of heat shock protein 72 (Hsp72) expression and activity on stress-induced apoptosis in CD30+ NPM–ALK+ anaplastic large-cell lymphomas

• Published in: Leukemia Vol. 26; no. 6; pp. 1375 - 1382
• Main Authors: Bonvini, P, Zorzi, E, Mussolin, L, Pillon, M, Romualdi, C, Peron, M, d'Amore, E S G, Lamant, L, Rosolen, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2012; Nature Publishing Group
• Subjects: 631/208/199; 631/45/612/1241; 631/80/82/23; 692/699/67/1990/291; Apoptosis; Bax protein; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blotting, Western; Cancer; Cancer Research; CD30 antigen; Cell activation; Cell cycle; Cell growth; Cell injury; Cell Proliferation; Cellular stress response; Child; Chromosome aberrations; Critical Care Medicine; Down-Regulation; Gene Expression Profiling; Heat shock proteins; Hematologic and hematopoietic diseases; Hematology; HSP72 Heat-Shock Proteins - genetics; HSP72 Heat-Shock Proteins - metabolism; Hsp72 protein; Humans; Immunoenzyme Techniques; Injury prevention; Intensive; Internal Medicine; Kinases; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma; Lymphoma, Large-Cell, Anaplastic - metabolism; Lymphoma, Large-Cell, Anaplastic - pathology; Medical genetics; Medical prognosis; Medical sciences; Medicine; Medicine & Public Health; Mitochondria; Mitochondria - pathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oligonucleotide Array Sequence Analysis; Oncology; original-article; Pathology; Phenotypes; Phosphorylation; Polypeptides; Real-Time Polymerase Chain Reaction; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal Transduction; Tissue Array Analysis; Toxicity; Tumorigenesis; Tumors; France; Italy; NPM–ALK; anaplastic large-cell lymphoma; heat shock proteins; Chromosomal aberration; NPM-ALK; Hematology; Anaplastic cell lymphoma; Malignant hemopathy; Large cell lymphoma; Non Hodgkin lymphoma; Biological activity; Stress; Abnormal chromosome B5; Cell death; Lymphoproliferative syndrome; Abnormal chromosome A2; Heat shock protein; Abnormal chromosome; Heat shock protein 72; Hybrid gene; Cancer; Apoptosis; Chromosome translocation
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2011.367

Understanding the mechanisms that control stress-induced apoptosis is critical to explain how tumours respond to treatment, as cancer cells frequently escape drug toxicity by regulating stress response through heat shock protein (HSP) expression. The overexpression of Hsp72, in particular, results in increased incidence of cell transformation, and correlates with poor prognosis in a wide range of cancers. We have shown that Hsp72 assists folding of oncogenic NPM–ALK kinase in anaplastic large-cell lymphomas (ALCLs), but its role in the maintenance of the malignant phenotype remains uncertain. Therefore, we assessed Hsp72 expression in ALCLs, investigating more in detail the mechanisms that regulate its status and activity. We found that Hsp72 is unique among the HSPs involved in tumourigenesis to be overexpressed in ALK + tumours and cell lines and to be induced by stress. Different from other HSPs, Hsp72 prevents cell injury, Bax activation and death by apoptosis in ALK + cells, acting both upstream and downstream of mitochondria. Conversely, Hsp72 is underexpressed in ALK − ALCL cells, and it is unable to protect cells from apoptosis under stress. Moreover, when Hsp72 expression is reduced following NPM–ALK inhibition, lymphoma cells undergo apoptosis, demonstrating the importance of Hsp72 in regulating ALCL stress response and drug sensitivity.