Reference Detail

Ref Type

Journal Article

PMID

(31697804)

Authors

Patel AB, Franzini A, Leroy E, Kim SJ, Pomicter AD, Genet L, Xiao M, Yan D, Ahmann JM, Agarwal AM, Clair P, Addada J, Lambert J, Salmon M, Gleich GJ, Cross NCP, Constantinescu SN, O'Hare T, Prchal JT, Deininger MW

Title

JAK2 ex13InDel drives oncogenic transformation and is associated with chronic eosinophilic leukemia and polycythemia vera.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood	134	26	2019 Dec 26	2388-2398	Blood

URL

Abstract Text

The V617F mutation in the JH2 domain of Janus kinase 2 (JAK2) is an oncogenic driver in several myeloproliferative neoplasms (MPNs), including essential thrombocythemia, myelofibrosis, and polycythemia vera (PV). Other mutations in JAK2 have been identified in MPNs, most notably exon 12 mutations in PV. Here, we describe a novel recurrent mutation characterized by a common 4-amino-acid deletion and variable 1-amino-acid insertion (Leu583-Ala586DelInsSer/Gln/Pro) within the JH2 domain of JAK2. All 4 affected patients had eosinophilia, and both patients with Leu583-Ala586DelInsSer fulfilled diagnostic criteria of both PV and chronic eosinophilic leukemia (CEL). Computational and functional studies revealed that Leu583-Ala586DelInsSer (herein referred to as JAK2ex13InDel) deregulates JAK2 through a mechanism similar to JAK2V617F, activates signal transducer and activator of transcription 5 and extracellular signal-regulated kinase, and transforms parental Ba/F3 cells to growth factor independence. In contrast to JAK2V617F, JAK2ex13InDel does not require an exogenous homodimeric type 1 cytokine receptor to transform Ba/F3 cells and is capable of activating β common chain family cytokine receptor (interleukin-3 receptor [IL-3R], IL-5R, and granulocyte-macrophage colony stimulating factor receptor) signaling in the absence of ligand, with the maximum effect observed for IL-5R, consistent with the clinical phenotype of eosinophilia. Recognizing this new PV/CEL-overlap MPN has significant clinical implications, as both PV and CEL patients are at high risk for thrombosis, and concomitant cytoreduction of red cells, neutrophils, and eosinophils may be required for prevention of thromboembolic events. Targeted next-generation sequencing for genes recurrently mutated in myeloid malignancies in patients with unexplained eosinophilia may reveal additional cases of Leu583-Ala586DelInsSer/Gln/Pro, allowing for complete characterization of this unique MPN.

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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	L583_A586delinsP	indel	unknown	JAK2 L583_A586delinsP results in a deletion of four amino acids of the Jak2 protein from amino acids 583 to 586, combined with the insertion of a proline (P) at the same site (UniProt.org). L583_A586delinsP has been identified in the scientific literature (PMID: 31697804), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Nov 2024).
JAK2	L583_A586delinsQ	indel	unknown	JAK2 L583_A586delinsQ results in a deletion of four amino acids of the Jak2 protein from amino acids 583 to 586, combined with the insertion of a glutamine (Q) at the same site (UniProt.org). L583_A586delinsQ has been identified in the scientific literature (PMID: 31697804), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Nov 2024).
JAK2	L583_A586delinsS	indel	gain of function	JAK2 L583_A586delinsS results in a deletion of four amino acids of the Jak2 protein from amino acids 583 to 586, combined with the insertion of a serine (S) at the same site (UniProt.org). L583_A586delinsS confers a gain of function to the Jak2 protein as indicated by ligand-independent cell growth and activation of Stat5, Erk1/2, and beta common chain-associated cytokine receptor signaling, and has been demonstrated to confer resistance to Jak2 inhibitors in cultured cells (PMID: 31697804).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
JAK2 L583_A586delinsS	hematologic cancer	resistant	Momelotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing JAK2 L583_A586delinsS demonstrated resistance to inhibition of cell proliferation by Momelotinib (CYT387) in culture (PMID: 31697804).	31697804
JAK2 L583_A586delinsS	hematologic cancer	resistant	Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing JAK2 L583_A586delinsS demonstrated resistance to inhibition of cell proliferation by Jakafi (ruxolitinib) in culture (PMID: 31697804).	31697804