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Supplementary Figure 4 from Characterization of Rearrangements Involving the ALK Gene Reveals a Novel Truncated Form Associated with Tumor Aggressiveness in Neuroblastoma

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posted on 2023-03-30, 21:48 authored by Alex Cazes, Caroline Louis-Brennetot, Pierre Mazot, Florent Dingli, Bérangère Lombard, Valentina Boeva, Romain Daveau, Julie Cappo, Valérie Combaret, Gudrun Schleiermacher, Stéphanie Jouannet, Sandrine Ferrand, Gaëlle Pierron, Emmanuel Barillot, Damarys Loew, Marc Vigny, Olivier Delattre, Isabelle Janoueix-Lerosey

PDF file - 144K, Insert size distributions of fragment lengths after capture and paired-end sequencing for the 10 samples studied

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ARTICLE ABSTRACT

Activating mutations of the ALK gene have been identified in sporadic and familial cases of neuroblastoma (NB), a cancer of the peripheral nervous system, and are thought to be the primary mechanism of oncogenic activation of this receptor in this pediatric neoplasm. To address the possibility that ALK activation may occur through genomic rearrangements as detected in other cancers, we first took advantage of high-resolution array-comparative genomic hybridization to search for ALK rearrangements in NB samples. Using complementary experiments by capture/paired-end sequencing and FISH experiments, various types of rearrangements were fully characterized, including partial gains or amplifications, in several NB cell lines and primary tumors. In the CLB-Bar cell line, we described a genomic rearrangement associated with an amplification of the ALK locus, leading to the expression of a 170 kDa protein lacking part of the extracellular domain encoded by exons 4 to 11, named ALKΔ4-11. Analysis of genomic DNA from the tumor at diagnosis and relapse revealed that the ALK gene was amplified at diagnosis but that the rearranged ALK allele was observed at the relapse stage only, suggesting that it may be implicated in tumor aggressiveness. Consistently, oncogenic and tumorigenic properties of the ALKΔ4-11 variant were shown after stable expression in NIH3T3 cells. Moreover, we documented an increased constitutive kinase activity of this variant, as well as an impaired maturation and retention into intracellular compartments. These results indicate that genomic rearrangements constitute an alternative mechanism to ALK point mutations resulting in receptor activation. Cancer Res; 73(1); 195–204. ©2012 AACR.

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