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. 2015 Sep 29:6:8470.
doi: 10.1038/ncomms9470.

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

Mark J Kiel  1 , Anagh A Sahasrabuddhe  1 , Delphine C M Rolland  2 , Thirunavukkarasu Velusamy  1 , Fuzon Chung  1 , Matthew Schaller  1 , Nathanael G Bailey  1 , Bryan L Betz  1 , Roberto N Miranda  3 , Pierluigi Porcu  4 , John C Byrd  4 , L Jeffrey Medeiros  3 , Steven L Kunkel  1 , David W Bahler  5 , Megan S Lim  2 , Kojo S J Elenitoba-Johnson  2   6
Affiliations

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

Mark J Kiel et al. Nat Commun. .

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.

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Figures

Figure 1
Figure 1. Structural alterations in six Sézary syndrome genomes identified by whole-genome sequencing.
Circos diagrams for six SS genomes: panels a (case A02), b (case B02), c (case C02), d (case D02), e (case G01) and f (case H01) depict the chromosomes arranged circularly end to end with each chromosome's cytobands marked in the outer ring. The inner ring displays copy-number data inferred from whole-genome sequencing with blue indicating losses and red indicating gains. Within the circle, rearrangements are shown as arcs with intrachromosomal events in red and interchromosomal translocations in blue. The two representative translocations involving EZH2-FOXP1 and ZEB1-CBLB are highlighted in c and d, respectively.
Figure 2
Figure 2. Recurrent loss-of-function alterations of chromatin remodelers and DNA modifier genes.
Evidence of loss of function in Sézary syndrome (SS) genomes including (i) proportion of total genome locus affected, (ii) depiction of individual genomes of SS with very narrowly defined deletions specifically targeting the highlighted gene and (iii) deleterious mutations including frameshift and missense mutations confirmed to be somatic by Sanger sequencing for (a) ARID1A, (b) ZEB1, (c) NCOR1 and (d) TET2.
Figure 3
Figure 3. Epigenetic modifiers and JAK–STAT pathway components are targeted by aneuploidy and mutations.
Summary of deletions and/or mutations in SS genomes affecting genes involved in epigenetic modifications. The loss-of-function of epigenetic modifiers including ARID family members, TETs, DNMTs, NCOR1, MLLs and SET domain containing genes are indicated in blue while gain-of-function mutations in JAK and STAT family members are indicated in red.
Figure 4
Figure 4. Validation of gain-of-function of JAK–STAT pathway in Sézary syndrome (SS).
(a) Schematic representations of mutations in JAK1, JAK3, STAT3 and STAT5B identified in primary SS samples and the Hut-78 SS-derived cell line. (b) Dose–response curves for two primary SS leukaemic cells (SS29 and SS87), the negative control cell lines (HH and Jurkat) and the positive control cell line (Mac-1) after 48 h of treatment with JAK inhibitor I. All experiments were performed in triplicate and error bars represent s.d's (***P<0.001, T-test). (c) Time–response curve for the two primary Sézary syndrome leukaemic cells (SS29 and SS87), the negative control cell lines (HH and Jurkat) and the positive control cell line (Mac-1) treated with 3 μM of JAK inhibitor I. All experiments were performed in triplicate and error bars represent s.d.'s (**P<0.01 and ***P<0.001 T-test). (d) Phosphorylation of STAT1, STAT3 and STAT5 in the two primary SS leukaemic cells (SS29 and SS87), the negative control cell lines (HH and Jurkat) and the positive control cell line (Mac-1) treated with 3 μM of JAK inhibitor I for 4 h.
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