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	Vol	Issue	Date	Pages	Journal Short Title
Blood	123	9	2014 Feb 27	1372-83	Blood

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

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
JAK2	R867Q	missense	gain of function	JAK2 R867Q lies within the 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).
JAK2	R938Q	missense	gain of function	JAK2 R938Q lies within the 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
JAK2	S755R	missense	gain of function - predicted	JAK2 S755R lies within 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	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	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	Fedratinib	Preclinical - Cell culture	Actionable	In a preclinical study, immune cells expressing JAK2 R867Q demonstrated decreased response to Inrebic (fedratinib) 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