Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Nature communications	6		2015 09 29	8470	Nat Commun

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
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 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, Dec 2024).
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, PMID: 25801821), but has not been biochemically characterized and therefore, its effect on Jak3 protein function is unknown (PubMed, Dec 2024).
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, Dec 2024).

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 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
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