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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 Blood
Vol 134
Issue 26
Date 2019 Dec 26
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 from amino acids 583 to 586 of the Jak2 protein, 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, Jul 2020).
JAK2 L583_A586delinsQ indel unknown JAK2 L583_A586delinsQ results in a deletion of four amino acids from amino acids 583 to 586 of the Jak2 protein, 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, Jul 2020).
JAK2 L583_A586delinsS indel gain of function JAK2 L583_A586delinsS results in a deletion of four amino acids from amino acids 583 to 586 of the Jak2 protein, 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