Reference Detail

Ref Type

Journal Article

PMID

(36786170)

Authors

Lahera A, López-Nieva P, Alarcón H, Marín-Rubio JL, Cobos-Fernández MÁ, Fernández-Navarro P, Fernández AF, Vela-Martín L, Sastre I, Ruiz-García S, Llamas P, López-Lorenzo JL, Cornago J, Santos J, Fernández-Piqueras J, Villa-Morales M

Title

SOCS3 deregulation contributes to aberrant activation of the JAK/STAT pathway in precursor T-cell neoplasms.

Journal	Vol	Issue	Date	Pages	Journal Short Title
British journal of haematology	201	4	2023 May	718-724	Br J Haematol

URL

Abstract Text

Despite the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway being frequently altered in T-ALL/LBL, no specific therapy has been approved for T-ALL/LBL patients with constitutive signalling by JAK/STAT, so there is an urgent need to identify pathway members that may be potential therapeutic targets. In the present study, we searched for JAK/STAT pathway members potentially modulated through aberrant methylation and identified SOCS3 hypermethylation as a recurrent event in T-ALL/LBL. Additionally, we explored the implications of SOCS3 deregulation in T-ALL/LBL and demonstrated that SOCS3 counteracts the constitutive activation of the JAK/STAT pathway through different molecular mechanisms. Therefore, SOCS3 emerges as a potential therapeutic target in T-ALL/LBL.

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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	D604Y	missense	gain of function	JAK1 D604Y lies within protein kinase domain 1 of the Jak1 protein (UniProt.org). D604Y (corresponds to D603Y in mouse) confers a gain of function to Jak1 as demonstrated by cytokine-independent cell proliferation (PMID: 25855603, PMID: 36786170) and increased Stat1 and Stat5 phosphorylation in culture (PMID: 36786170).
JAK1	F805V	missense	gain of function	JAK1 F805V lies within protein kinase domain 1 of the Jak1 protein (UniProt.org). F805V confers a gain of function to Jak1 as demonstrated by increased Stat1 and Stat5 phosphorylation and cytokine-independent growth in cultured cells (PMID: 36786170).
JAK1	L653F	missense	gain of function	JAK1 L653F lies within protein kinase domain 1 of the Jak1 protein (UniProt.org). L653F (corresponds to L652F in mouse) confers a gain of function to Jak1 as demonstrated by cytokine-independent cell proliferation (PMID: 25855603, PMID: 36786170) and increased Stat1 and Stat5 phosphorylation in culture (PMID: 36786170).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
JAK1 L653F	hematologic cancer	sensitive	Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, Jakafi (ruxolitinib) inhibited Stat5 phosphorylation and viability in a cell line expressing JAK1 L653F in culture (PMID: 36786170).	36786170
JAK1 D604Y	hematologic cancer	sensitive	Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, Jakafi (ruxolitinib) inhibited Stat5 phosphorylation and viability in a cell line expressing JAK1 D604Y in culture (PMID: 36786170).	36786170
JAK1 V658F	hematologic cancer	sensitive	Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, Jakafi (ruxolitinib) inhibited Stat5 phosphorylation and viability in a cell line expressing JAK1 V658F in culture (PMID: 36786170).	36786170
JAK1 F805V	hematologic cancer	sensitive	Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, Jakafi (ruxolitinib) inhibited Stat5 phosphorylation and viability in a cell line expressing JAK1 F805V in culture (PMID: 36786170).	36786170