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A.N. Bastidas Torres et al.
data,5 we found that gains within 7q and 17q as well as losses within 1p and 13q were the most common large- scale chromosomal imbalances.
Our analysis identified a group of bona fide oncogenes and tumor suppressors with central roles in the cell cycle (i.e., CDKN2A/B, MIR34AHG, MYC, RB1, TP53), chro- matin regulation (i.e., ARID1A, BAZ1A, EED, EPC1, KMT2D, NCOR1, ZEB1) and the JAK-STAT pathway (i.e., JAK2, JAK3, PTPRC, SH2B3, SOCS1, STAT3, STAT5B) whose copy number, sequence organization and/or nucleotide composition were found to be recurrently altered in our pcAECyTCL cohort. Genetic alterations involving JAK-STAT pathway genes were the most notable due to their predominance, likely proliferation- promoting effects and known causative roles in hemato- logical cancers. A subset of SNV affecting JAK-STAT path- way genes in pcAECyTCL have confirmed oncogenic activity in other T-cell lymphomas (Table 1).27,28
JAK2 and SH2B3, which govern the activation and ter- mination of JAK2 signaling in normal hematopoietic cells, respectively, underwent mutually exclusive alterations in nine of 12 patients from our cohort. Mutations in these two genes are associated with BCR-ABL1– myeloprolifer- ative neoplasms (MPN), a group of myeloid malignancies driven by overactive JAK2 signaling.11,29 However, unlike BCR-ABL1– MPN where JAK2 and SH2B3 are mainly affected by pathogenic SNV and/or indels, these two genes experienced predominantly structural alterations in pcAECyTCL. On one hand, JAK2 formed fusion genes encoding self-activating chimeras. On the other hand, SH2B3 was inactivated by focal interstitial deletions and unbalanced rearrangements. The previous suggests that pcAECyTCL is mainly driven by aberrant JAK2 signaling resulting from oncogenic changes leading to JAK2 overac- tivation or SH2B3 deficiency. Moreover, we demonstrated that JAK2 fusions found in pcAECyTCL promote cytokine-independent cell survival and their oncogenic activity was shown to be successfully inhibited by ruxoli- tinib. Of note, JAK2 fusions functionally analogous to the ones identified in pcAECyTCL have been previously described and confirmed as oncogenic in other hemato- logical malignancies (e.g., B- and T-cell acute leukemias, MPN).20 Also, recurrent deletion of SH2B3 has been reported in an aggressive subtype of B-cell precursor acute lymphoblastic leukemia.30
We found that genetic alterations involving JAK2 and SH2B3 co-existed with SNV predicted or confirmed as pathogenic in STAT3 or STAT5B in six of nine affected patients. Previous functional in vitro studies with cell lines have suggested that mutations in STAT proteins (espe- cially dimerization-enhancing SNV) observed in T-cell lymphomas operate as aberrant amplifiers of upstream signals from cytokines, overactive receptors or deregulat- ed JAK proteins, rather than as initiators of deregulated JAK-STAT signaling themselves.27 In this scenario, muta- tions in STAT3/5B would contribute to pcAECyTCL pro- gression by making the pre-existing overactive JAK2 sig- naling more robust and severe. However, recent evidence derived from a murine model suggests that at least gain- of-function mutation STAT5B (p.N642H), one of the most common pathogenic SNV in human T-cell lym- phomas,31 is sufficient by itself to promote the develop- ment of neoplasms primarily derived from mature CD8+ T cells.32 Remarkably, malignant CD8+ T cells in these animals showed preferential migration to the skin, lung
and the central nervous system, all of which are com- monly affected body sites in pcAECyTCL.32 Consistent with this evidence, patient AEC1, the only individual in our cohort who had a single JAK-STAT pathway gene mutated, carried the STAT5B (p.N642H) mutation biallel- ically.
Several pathogenetic features found in pcAECyTCL have also been reported in mycosis fungoides (MF) and/or Sézary syndrome (SS). Genetic alterations common to pcAECyTCL, MF and SS include recurrent inactivation of ARID1A, CDKN2A, CDKN2B, NCOR1, PTPRC, TP53 and ZEB1 as well as occasional activating mutations in JAK3, MYC and STAT3.33-39 Other genetic alterations observed in pcAECyTCL have been found before either in MF (e.g., SOCS1 and STK11 inactivation) or SS (e.g., RB1 inactiva- tion, STAT5B mutations).33,34,39 By contrast, JAK2 fusions and SH2B3 inactivation have not been reported in other CTCL variants to the best of our knowledge and appear to be characteristic features of pcAECyTCL.
In agreement with the recurrent genetic alterations involving the JAK2-SH2B3 signaling axis observed in pcAECyTCL, transcriptome analysis revealed upregula- tion of JAK2 signaling. SH2B1 and PTPN11, which encode two proteins with the ability to enhance JAK2 signal- ing,40,41 stood out among upregulated JAK-STAT pathway genes. Adaptor protein SH2B1 has been proven to bind to JAK2 and stimulate its kinase activity.42 Similarly, phos- phatase PTPN11 (SHP-2) has been shown to positively regulate JAK2-mediated STAT5 phosphorylation.43 In con- trast, phosphatase PTPRC (CD45), whose expression has been shown to attenuate JAK2 signaling in hematopoietic and lymphoma cells,44,45 was downregulated in pcAECyTCL. Yet, the exact molecular interactions under- lying the action of these three regulators of JAK2 signaling remain to be fully elucidated.
Transcriptome analysis also revealed upregulation of the cell cycle, the TNF-α/NF-κB pathway and a high inflam- matory response in pcAECyTCL. Notably, the co-activa- tion (crosstalk) of JAK-STAT signaling (especially via STAT3) and NF-κB signaling is a well-documented phe- nomenon in cancer, and it has been shown to promote a pro-oncogenic inflammatory microenvironment in the tumor.46 For instance, aberrant JAK2 signaling (via STAT3) in MPN promotes chromatin changes that induce NF-κB signaling; and the resulting combined action of these two pathways, appear to drive the characteristic chronic inflammatory state observed in these neoplasms.47 Our data, in line with the previous, suggest that co-activation of JAK2 signaling and NF-κB signaling operates in pcAECyTCL as well, and their joint action might be responsible for the inflammatory state detected in pcAECyTCL tumors.
Taken together, our findings strongly suggest that over- activation of JAK2 signaling plays a pivotal role in the pathogenesis of pcAECyTCL. Therefore, patients with this lymphoma would likely benefit from treatment with JAK2 inhibitors (e.g., FDA-approved ruxolitinib). In addi- tion, the potential combination of JAK2 inhibitors with NF-κB inhibitors (e.g. bortezomib,48 dimethyl fumarate49) represents an attractive possibility since targeting both pathways might have a synergistic effect and reduce the chance of resistance acquisition.
Disclosures
No conflicts of interest to disclose.
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haematologica | 2022; 107(3)