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Ref Type Journal Article
PMID (26415585)
Authors Kiel MJ, Sahasrabuddhe AA, Rolland DC, Velusamy T, Chung F, Schaller M, Bailey NG, Betz BL, Miranda RN, Porcu P, Byrd JC, Medeiros LJ, Kunkel SL, Bahler DW, Lim MS, Elenitoba-Johnson KS
Title Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sézary syndrome.
Journal Nature communications
Vol 6
Issue
Date 2015 09 29
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
JAK1 L710V missense unknown JAK1 L710V lies within protein kinase domain 1 of the Jak1 protein (UniProt.org). L710V results in constitutive activation of JAK-STAT signaling in cell culture when combined with STAT3 I498V (PMID: 26415585), but has not been individually characterized and therefore, its effect on Jak1 protein function is unknown.
JAK1 Y654F missense gain of function - predicted JAK1 Y654F lies within the protein kinase domain 1 of the Jak1 protein (UniProt.org). Y654F demonstrated constitutive activation of JAK-STAT signaling in primary cells in culture (PMID: 26415585), and therefore, is predicted to lead to a gain of Jak1 protein function.
JAK3 S989I missense unknown JAK3 S989I lies within protein kinase domain 2 of the Jak3 protein (UniProt.org). S989I has been identified in the scientific literature (PMID: 26415585), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2022).
JAK3 Y1023H missense unknown JAK3 Y1023H lies within protein kinase domain 2 of the Jak3 protein (UniProt.org). Y1023H has been identified in sequencing studies (PMID: 26415585), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, May 2022).
TET2 P174H missense unknown TET2 P174H does not lie within any known functional domains of the Tet2 protein (UniProt.org). P174H has been identified in sequencing studies (PMID: 26415585), but has not been biochemically characterized and therefore, its effect on Tet2 protein function is unknown (PubMed, Apr 2022).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK1 Y654F Sezary's disease sensitive Pyridone 6 Preclinical - Cell culture Actionable In a preclinical study, Pyridone 6 (CMP6) inhibited proliferation of cells derived from a Sezary syndrome patient harboring JAK1 Y654F in culture (PMID: 26415585). 26415585
JAK1 Y654F Sezary's disease sensitive Ruxolitinib Preclinical - Patient cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) inhibited growth of primary cells derived from a Sezary syndrome patient harboring JAK1 Y654F in culture (PMID: 26415585). 26415585
JAK1 Y654F JAK3 A573V Sezary's disease sensitive Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) inhibited growth of a Sezary syndrome cell line harboring JAK1 Y654F and JAK3 A573V in culture (PMID: 26415585). 26415585