Reference Detail

Ref Type Journal Article
PMID (24398328)
Authors Marty C, Saint-Martin C, Pecquet C, Grosjean S, Saliba J, Mouton C, Leroy E, Harutyunyan AS, Abgrall JF, Favier R, Toussaint A, Solary E, Kralovics R, Constantinescu SN, Najman A, Vainchenker W, Plo I, Bellanne-Chantelot C
Title Germ-line JAK2 mutations in the kinase domain are responsible for hereditary thrombocytosis and are resistant to JAK2 and HSP90 inhibitors.
Journal Blood
Vol 123
Issue 9
Date 2014 Feb 27
URL
Abstract Text The main molecular basis of essential thrombocythemia and hereditary thrombocytosis is acquired, and germ-line-activating mutations affect the thrombopoietin signaling axis. We have identified 2 families with hereditary thrombocytosis presenting novel heterozygous germ-line mutations of JAK2. One family carries the JAK2 R867Q mutation located in the kinase domain, whereas the other presents 2 JAK2 mutations, S755R/R938Q, located in cis in both the pseudokinase and kinase domains. Expression of Janus kinase 2 (JAK2) R867Q and S755R/R938Q induced spontaneous growth of Ba/F3-thrombopoietin receptor (MPL) but not of Ba/F3-human receptor of erythropoietin cells. Interestingly, both Ba/F3-MPL cells expressing the mutants and platelets from patients displayed thrombopoietin-independent phosphorylation of signal transducer and activator of transcription 1. The JAK2 R867Q and S755R/R938Q proteins had significantly longer half-lives compared with JAK2 V617F. The longer half-lives correlated with increased binding to the heat shock protein 90 (HSP90) chaperone and with higher MPL cell-surface expression. Moreover, these mutants were less sensitive to JAK2 and HSP90 inhibitors than JAK2 V617F. Our results suggest that the mutations in the kinase domain of JAK2 may confer a weak activation of signaling specifically dependent on MPL while inducing a decreased sensitivity to clinically available JAK2 inhibitors.

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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
Variant Impact Protein Effect Variant Description Associated with drug Resistance
R867Q missense gain of function JAK2 R867Q lies within the JH1 protein kinase domain 2 of the Jak2 protein (UniProt.org). R867Q results in constitutive activation of STAT3/5, AKT and ERK signaling, and increased proliferation in thrombopoietin receptor-expressing cells in culture (PMID: 24398328).
R938Q missense gain of function JAK2 R938Q lies within the JH1 protein kinase domain 2 of the Jak2 protein (UniProt.org). R938Q confers a gain of function to the Jak2 protein, as demonstrated by constitutive Stat5 signaling (PMID: 29025600), transformation of cultured cells (PMID: 24398328), and also displays resistance to Jak1/2 ATP-competitive inhibitors (PMID: 29025600). Y
S755R missense gain of function - predicted JAK2 S755R lies within the protein kinase domain 1 of the Jak2 protein (UniProt.org). S755R demonstrates basal activity similar to wild-type Jak2 but increased Akt phosphorylation and cell growth when stimulated with high level thrombopoietin (PMID: 24398328), and therefore, is predicted to lead to a gain of Jak2 protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK2 R867Q hematologic cancer decreased response Ruxolitinib Preclinical Actionable In a preclinical study, immune cells expressing JAK2 R867Q demonstrated decreased response to Jakafi (ruxolitinib) in culture (PMID: 24398328). 24398328
JAK2 R867Q hematologic cancer decreased response Momelotinib Preclinical Actionable In a preclinical study, immune cells expressing JAK2 R867Q demonstrated decreased response to Momelotinib (CYT387) in culture (PMID: 24398328). 24398328
JAK2 R867Q hematologic cancer decreased response Luminespib Preclinical Actionable In a preclinical study, immune cells expressing JAK2 R867Q demonstrated decreased response to Luminespib (AUY922) in culture (PMID: 24398328). 24398328
JAK2 R867Q hematologic cancer decreased response AZ960 Preclinical Actionable In a preclinical study, immune cells expressing JAK2 R867Q demonstrated decreased response to AZ960 in culture (PMID: 24398328). 24398328
JAK2 R867Q hematologic cancer decreased response SAR302503 Preclinical - Cell culture Actionable In a preclinical study, immune cells expressing JAK2 R867Q demonstrated decreased response to Fedratinib (SAR302503) in culture (PMID: 24398328). 24398328