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A.N. Bastidas Torres et al.
Figure 1. Landscape of genomic rearrangements in pcAECyTCL. Circos plot showing 426 genomic rearrangements detected in twelve pcAECyTCL genomes by whole- genome sequencing (WGS). The outer ring shows rearranged genes with established roles in cancer. The area at the center of the plot con- tains arcs representing interchromo- somal (blue) and intrachromosomal (red) events. The ring between the gene labels and the arcs contains human chromosome ideograms arranged circularly end to end. pcAECyTCL: primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma.
in three of 12 patients (i.e., AEC4: KHDRBS1-JAK2; AEC9: PCM1-JAK2; AEC11: TFG-JAK2) (Figure 2F to H). These events fused the tyrosine kinase domain of JAK2 with one or more oligo/dimerization domains from the fusion part- ner (i.e., AEC4: Qua1 domain, AEC9: coiled-coil domains, AEC11: PB1 domain) (Figure 2F to H). The resulting chimeric proteins are predicted to self-oligo/dimerize and become activated without the need of cytokine-mediated receptor stimulation, ultimately overactivating JAK2 sig- naling. Of note, two of three patients carrying JAK2 fusions carried MYC fusions as well (i.e., AEC4: ACTB- MYC, AEC9: NPM1-MYC) (Online Supplementary Figure S4). Interestingly, apart from acquiring the ability to self- activate, JAK2 fusions under the transcriptional control of their partner’s promoter may also experience augmented expression in comparison to wild-type JAK2, as evidenced in patient AEC4 (Figure 2I). In contrast, rearrangements involving PTPRC and SH2B3, each observed in two of 12 patients, disrupted these two negative regulators of the JAK-STAT pathway.
JAK2 signaling inhibitor SH2B3 is focally deleted in pcAECyTCL
The most frequent broad chromosomal imbalances (npa- tients≥4; >3 Mb) were deletions within 1p, 8p, 9q, 10p, 11q and 13q and gains within 7q, 8q, 17q and 21q (Figure 3A; Figure 4A). We identified 24 recurrent focal (≤ 3 Mb) min- imal common regions (MCR) shared by CNA between patients (npatients≥3; deletions: 19, gains: 5) (Online Supplementary Table S5), 12 of which contained cancer genes predominantly involved in the cell cycle, chromatin regulation and the JAK-STAT pathway (Figure 4A).
The most common focal MCR involving cancer genes
was deletion at 9p21.3 (10 patients), which included cell cycle regulators CDKN2A/B (Online Supplementary Figure S7). Of note, CDKN2A/B were found to be inactivated by interstitial deletions, unbalanced rearrangements, SNV and presumably even the action of long non-coding RNA ANRIL (CDKN2B-AS1)9 (Figure 4A; Online Supplementary Figure S11). Five of 12 patients had deletions at 1p36.11 and 13q14.11, which contained chromatin remodeler ARID1A and candidate cancer gene ELF1,10 respectively. Deletions at 1p36.32-p36.33, 1p36.22 and 12q24.12, observed in four of 12 patients, involved tumor suppres- sors TNFRSF14, MIR34AHG and SH2B3, respectively. Finally, three of 12 patients had deletions at 4q13.1-q13.2, 10p11.22, 11q14.2, 16p13.13 and 19p13.3, which con- tained tumor suppressors EPHA5, EPC1 (alongside ZEB1), EED, SOCS1 and STK11, respectively. On the other hand, gain at 17q21.31 (four patients), which enclosed ETV4, was the only recurrent (npatients ≥3) focal gain containing a cancer gene.
Remarkably, deletions at 12q24.12 were strikingly focal in all affected patients (20 Kb – 457 Kb), leading to the loss of one or more functional domains of SH2B3 (i.e., DD, PH, SH2 domains) in these individuals (Figure 3B and C; Online Supplementary Figure S5). SH2B3 (LNK) encodes an adaptor protein that antagonizes JAK2 signaling as part of a nega- tive feedback loop in various hematopoietic cell types (e.g., erythroid progenitors, hematopoietic stem cells, megakaryocytes, pre-B cells, etc.) by suppressing the kinase activity of JAK2 through its SH2 domain.11 Of note, structural alterations involving JAK2 and SH2B3 were mutually exclusive in our cohort, affecting altogether seven of 12 patients. In addition, we investigated the pos- sibility of SH2B3 silencing by promoter hypermethylation
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haematologica | 2022; 107(3)