ALK Anaplastic Large Cell Lymphomas Research Articles

Peripheral T-cell Lymphomas With Cytotoxic Phenotype in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is relatively common, and patients occasionally develop other neoplasms; however, patients who develop other types of lymphomas are rare. We encountered 3 patients with CLL/SLL (one 59-y-old man and 2 women aged 56 and 66 y) who developed T-cell lymphomas. Both women developed ALK anaplastic large cell lymphomas (ALCLs), whereas the man developed CD8 peripheral T-cell lymphoma, not otherwise specified. All 3 T-cell lymphomas expressed granzyme B and perforin, indicating a cytotoxic immunophenotype. In 1 case, the first presentation was a lymph nodal composite lymphoma. In the other 2 cases, the T-cell lymphomas arose <1 year after the diagnosis of CLL/SLL and were identified in a lymph node in one case and in the spleen in the other. The patient with a composite lymphoma (SLL/ALK ALCL) was treated and was free of disease at last follow-up, whereas the other 2 patients succumbed to their disease, 1 month and 7 months after the diagnosis of T-cell lymphoma. Peripheral T-cell lymphomas rarely occur in CLL/SLL patients. On the basis of our small series, those with a cytotoxic phenotype appear to be more common in this setting. The occurrence of ALK ALCL in 2 older patients was especially surprising and suggested that CLL/SLL may have played a role in the development of ALCL.

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

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.

Expression of the ALK protein by anaplastic large-cell lymphomas correlates with high proliferative activity.

A variable fraction of anaplastic large-cell lymphomas (ALCLs) exhibits a t(2;5)(p23;q35) translocation that results in expression of the chimeric hyperphosphorylated protein NPM-ALK (p80). Tumor cells expressing NPM-ALK exhibit markedly enhanced proliferative activity, but comparative cellular kinetic studies on ALK(+) (ALK lymphomas) and ALK(-) lymphomas are lacking. The present study showed that ALK(+) lymphomas, detected with the monoclonal antibody ALKc (n = 17), had significantly higher average values for the proliferation-associated parameters mitotic index, ana/telophase index, growth index (x x mitotic index - apoptotic index, assuming x = 3), percentages of Ki-67(+) cells and fraction of cells expressing cyclin A or B or the cell cycle-regulatory protein p34(cdc2) than did ALK(-) ALCLs (n = 15). Whether this intense proliferative activity contributes to the good response to chemotherapy and favorable outcome of ALK(+) ALCLs remains to be assessed in a larger series of patients. Our findings support the notion that ALK(+) and ALK(-) ALCLs are 2 distinct disease entities.