Anaplastic lymphoma kinase (ALK) gene rearrangement and chimeric nucleophosmin (NPM)-ALK fusion oncoprotein were first identified in anaplastic large cell lymphoma (ALCL).1 Fusion of ALK to other genes have subsequently been found in other neoplasms, including clathrin heavy chain 1 (CLTC-ALK) in diffuse large B-cell lymphoma (DLBCL) and echinoderm microtubule associated protein like 4 (EML4-ALK) in non-small-cell lung carcinoma (NSCLC).2, 3 ALK-positive DLBCL is uncommon but aggressive, accounting for <1% of all DLBCLs, with <100 cases reported since its first description in 1997.4 ALK-positive DLBCL have an inferior clinical outcome when treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-derived regimens.5 CLTC-ALK is the most common genetic fusion in ALK-positive DLBCL, arising from t(2;17) and resulting in the chimeric oncoprotein CLTC-ALK with a constitutively activated ALK kinase domain.6 A selective ALK kinase inhibitor suppressed the growth of CLTC-ALK-positive DLBCL cells in vitro and in vivo, indicating CLTC-ALK to be a potential therapeutic target in ALK-positive DLBCL.7 Arsenic trioxide (As2O3) exerts anti-leukaemic activity by targeting the promyelocytic leukaemia/retinoic acid receptor alpha (PML-RARA) oncoprotein for degradation in acute promyelocytic leukaemia (APL). It also induces degradation of the mutant cytoplasmic NPM, NPMc+, in acute myeloid leukaemia (AML).8 We therefore proposed that As2O3 might also target NPM-ALK in ALCL. Previous work in our group has shown that As2O3 induces degradation of NPM-ALK fusion protein in ALK-positive ALCL in vitro and in vivo, thereby suppressing tumour growth of ALK-positive ALCL.9 Here we further hypothesised that As2O3 might also exhibit anti-lymphoma effect in ALK-positive DLBCL by targeting the CLTC-ALK fusion protein. READ ARTICLE
British Journal of Haematology DOI: 10.1111/bjh.17581
Authors: Yue L.-M., Chau D., Kwong Y.-L. and Tse E.
Read More
