Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK–STAT pathway in Sézary syndrome

Abstract

Sézary syndrome (SS) is an aggressive leukaemia of mature T cells with poor prognosis and limited options for targeted therapies. The comprehensive genetic alterations underlying the pathogenesis of SS are unknown. Here we integrate whole-genome sequencing (n=6), whole-exome sequencing (n=66) and array comparative genomic hybridization-based copy-number analysis (n=80) of primary SS samples. We identify previously unknown recurrent loss-of-function aberrations targeting members of the chromatin remodelling/histone modification and trithorax families, including ARID1A in which functional loss from nonsense and frameshift mutations and/or targeted deletions is observed in 40.3% of SS genomes. We also identify recurrent gain-of-function mutations targeting PLCG1 (9%) and JAK1, JAK3, STAT3 and STAT5B (JAK/STAT total ∼11%). Functional studies reveal sensitivity of JAK1-mutated primary SS cells to JAK inhibitor treatment. These results highlight the complex genomic landscape of SS and a role for inhibition of JAK/STAT pathways for the treatment of SS.

Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell–derived lymphomas

“…[20][21][22][23][24]53 Nonetheless, mutations in specific genes are variably recurrent in distinct entites, 24,25 and for a given gene, the distribution of the mutations and their relative prevalence are G869E E730K S520F S345F D1165G D1165H E1163K D342G R48W E47K PH1 PI heterogeneous. For instance, PLCG1 and CARD11 mutations are highly prevalent (up to 18% and 15% of the cases, respectively) in cutaneous T-cell lymphoma, in which conversely CD28 mutations are not found.…”

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…Reports on patient mutation sequencing analyses of various T-cell lymphoma subtypes frequently include the JAK/STAT pathway, where JAK1, JAK3, STAT3 , and STAT5B are predominantly mutated to cause hyperactivation [64,70,75–78]. Importantly, ALK − ALCL is associated with STAT3 activation [64] and recurrent, somatic activating mutations in the closely related STAT5B gene were reported.…”

“…Importantly, ALK − ALCL is associated with STAT3 activation [64] and recurrent, somatic activating mutations in the closely related STAT5B gene were reported. The STAT5B N642H mutation occurs with the highest frequency in PTCL, whereby most mutations cluster in the SH 2 and C-terminal transactivation domain [70,75,78–82]. A recent study found that ~70% of T-PLL patients carry JAK-STAT hyperactivating mutations [70].…”

“…TET2 frameshift and nonsense mutations were frequently identified in AITL (~70%), PTCL-NOS (~60% in T FH cell marker expressing subtype), and CTCL (~10%) [75,96–98]. In AITL, IDH2 and TET2 mutations were detected in the same patients, which is not the case in myeloid malignancies [77].…”

“…In AITL, PTCL-NOS and CTCL subtypes, DNMT3A mutations cluster in the methyltransferase domain. Interestingly, only about 20% of these mutations are at position R882 [75,77,94,95,97], the variant commonly found in myeloid diseases acting as a negatively regulating hypomorphic protein [105]. Dnm3a -deficient mice develop a PTCL-like disease at a frequency of 12% and heterozygous animals at a rate of 10%, associated with hypomethylation and decreased TP53 activity [106].…”