A Novel ALK Isoform Arises via Alternative Transcription Initiation

Oncogenes have been shown to be activated by various genetic alterations, including mutations, translocations, and amplifications. However, whether oncogenes can also be activated by other mechanisms remains unclear. To address this question, Wiesner and colleagues used RNA sequencing to identify differential expression of exons encoding the kinase domains of receptor tyrosine kinases in metastatic melanoma and thyroid carcinoma. This analysis revealed a previously uncharacterized transcript of anaplastic lymphoma kinase (ALK) consisting of a fragment of intron 19 followed by exons 20–29 that resulted from alternative transcription initiation (ATI) via an active ATI site in intron 19. Analysis of tumor samples from The Cancer Genome Atlas indicated that this ALK isoform, referred to as ALK^ATI, was expressed in approximately 11% of melanomas and sporadically in other cancers, but not in normal tissues. Comprehensive genetic studies showed that ALK^ATI was expressed from both ALK alleles, independent of genomic aberrations at the ALK locus. Transcriptional activation of the ALK^ATI isoform resulted in expression of three distinct proteins, each of which contained the intact ALK intracellular tyrosine kinase domain but lacked the extracellular and transmembrane domains. These ALK^ATI proteins were activated via homodimerization and autophosphorylation and localized to both the nucleus and cytoplasm, in contrast to other ALK mutants that localized primarily to the cytoplasm. Expression of ALK^ATI was sufficient to induce growth factor–independent proliferation in vitro and promoted tumor growth in vivo, consistent with an oncogenic function. Pharmacologic ALK inhibitors such as crizotinib suppressed ALK^ATI phosphorylation and signaling and triggered regression of ALK^ATI-driven tumors. Furthermore, crizotinib treatment led to rapid tumor shrinkage and symptomatic improvement in a patient with ALK^ATI-expressing metastatic melanoma. These findings suggest an alternative mechanism for oncogene activation in cancer and support the notion that ALK inhibitors may be beneficial in patients with ALK^ATI-driven tumors.

Wiesner T, Lee W, Obenauf AC, Ran L, Murali R, Zhang QF, et al. Alternative transcription initiation leads to expression of a novel ALK isoform in cancer. Nature 2015;526:453–7.

• ©2015 American Association for Cancer Research.