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. 2020 Sep 11;10:14954. doi: 10.1038/s41598-020-70890-6

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© The Author(s) 2020

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Human ALK variants are suppressed by mutations in the identified candidate genes. (A) Schematic representation of the screening approach, testing (1) hALK with the ALKAL1 ligand, which leads to high levels of ALK signaling activity, (2) a constitutively active hALK-F1174L observed in neuroblastoma and (3) the NPM1::ALK oncogene found in anaplastic large cell lymphoma. Single copies of loss-of-function (lof) mutations in the identified candidate genes were tested for phenotypic modification in flies ectopically expressing one of three oncogenic variants of human ALK (hALK) under sevEP-Gal4 control. (B–E) Eyes of adult female flies expressing either wild-type hALK (B), wild-type hALK activated by ALKAL1 (C), the hALKF1174L activating point mutation (D) or the chimeric hNPM1::hALK protein (E) with sevEP-Gal4. Scale bar = 100 µm. (F) Venn diagram representation of the results of the hALK modifier screens: 28 alleles suppressed (S) the rough-eye phenotype of all hALK variants (corresponding to the 14-3-3-ε, 14-3-3ζ, Asx, Cul2, Dl, Duox, E2f1, eya, eyg, ksr, lilli, Mapmodulin, msk, pll, pnt, Ras85D, rolled, Sos, Star, Stat92E, Taf6, TfIIA-L, TFIIA-S, TFIIEa, tll, and wts loci). One allele affecting two of the predicted five EcR isoforms enhanced (E) the eye phenotype. Modifiers that did not affect all hALK variants are highlighted in the diagram.