Inactivating mutations of CASP10 gene in non-Hodgkin lymphomas

Abstract

Caspase 10 (Mch4/FLICE2) is a caspase homologous to caspase 8. A recent report described that inherited CASP10 gene mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome (ALPS). In this study, to explore the possibility that mutation of this gene might be involved in the development of nonHodgkin lymphoma (NHL), we have analyzed the entire coding region and all splice sites of the CASP10 gene for the detection of somatic mutations in 117 human NHLs. Overall, 17 NHLs (14.5%) were found to have CASP10 mutations, which were identified in the coding regions of the prodomain (n ‫؍‬ 3), the p17 large protease subunit (n ‫؍‬ 11), and the p12 small protease subunit (n ‫؍‬ 3). We expressed the tumor-derived caspase 10 mutants in 293 cells and found that apoptosis was suppressed. These data suggest that the inactivating mutations of the CASP10 gene might lead to the loss of its apoptotic function and contribute to the pathogenesis of some human NHLs. (Blood. 2002;99:4094-4099)

Caspase-10 involvement in cytotoxic drug-induced apoptosis of tumor cells

“…Altogether, our data indicate that, in cells exposed to cytotoxic drugs such as etoposide, caspase-10 activation plays a role in the caspase cascade triggered by cytochrome c when released from the mitochondria. Caspase-10 mutations identified in tumor cells of some patients with non-Hodgkin's lymphomas were proposed to play a role in lymphomagenesis (Shin et al, 2002a). The decreased expression of caspase-10 observed in some AML blast cells at the time of relapse may both contribute to disease progression and increase blast cell resistance to cytotoxic drugs, indicating a so far unidentified importance for this enzyme in malignant cells.…”

“…Acquired inactivating mutations of caspase-10 have been identified in tumor cells from patients with nonHodgkin's lymphomas (Shin et al, 2002a) and solid tumors (Harada et al, 2002;Park et al, 2002;Shin et al, 2002b). Chemotherapeutic agents such as etoposide and doxorubicin induce casp-10 gene transcription in a p53-dependent manner (Rikhof et al, 2003) and arsenic trioxide stimulates casp-10 gene transcription by promoting histone H3 phosphoacetylation in acute promyelocytic leukemia cells (Li et al, 2002).…”

Caspase function in programmed cell death

“…92 Recently, caspase-10, along with caspase-8, was shown to be essential for mediating NF-kB-dependent inflammatory responses in antiviral signalling. 93 Missense and inactivating mutations in casp10 gene have been reported to be associated with some cases of the autoimmune lymphoproliferative syndrome II (ALPS II), 94 non-Hodgkin lymphoma 95 and gastric cancer, 96 however it is unclear whether these mutations directly contribute to the disease phenotype.…”

The JAK2 V617F mutation in de novo acute myelogenous leukemias

“…Sequencing of the PCR products was carried out using the cyclic sequencing kit (PerkinElmer, Foster City, CA, USA). The procedures of PCR and SSCP analysis were performed as described previously (Shin et al, 2002). We also confirm the mutation by a direct sequencing.…”