NPM1ALK

NPM1-ALK, also written NPM-ALK, is a fusion oncoprotein created by a chromosomal translocation between the NPM1 gene on chromosome 5 and the ALK gene on chromosome 2, most often t(2;5)(p23;q35). The fusion combines the NPM1 oligomerization domain with the ALK kinase domain, leading to constitutive activation of ALK signaling and cytoplasmic localization of the fusion protein.

Mechanistically, the constitutive kinase activity drives oncogenic signaling through pathways such as JAK/STAT3, PI3K/AKT, and RAS/ERK, promoting cell proliferation and survival. The cytoplasmic localization and ALK activation are hallmarks of the NPM1-ALK fusion protein.

Clinical significance is most prominent in ALK-rearranged anaplastic large cell lymphoma (ALCL), where NPM1-ALK is a defining genetic lesion. The fusion is also reported, albeit rarely, in other solid tumors, whereas ALK rearrangements in non-small cell lung cancer more commonly involve other partners such as EML4.

Diagnosis relies on molecular and immunohistochemical methods. Detection methods include fluorescence in situ hybridization (FISH) and reverse-transcription PCR to identify the NPM1-ALK fusion transcript, as well as immunohistochemistry for ALK protein expression. Next-generation sequencing panels can detect ALK rearrangements as part of broader genomic testing.

Treatment for tumors harboring ALK rearrangements employs ALK inhibitors. Crizotinib, the first approved agent, is followed by second- and third-generation inhibitors such as ceritinib, alectinib, brigatinib, and lorlatinib, which can overcome resistance and offer selective activity against ALK-driven tumors. Prognosis in ALK-positive ALCL is generally favorable compared with ALK-negative disease, with outcomes influenced by tumor type and stage.