Appendix XIII: Tumor Associated Mutations in JAK2

Matthews, David J.; Gerritsen, Mary E.

doi:10.1002/9780470555293.app13

Targeting Protein Kinases for Cancer Therapy 2010

DOI: 10.1002/9780470555293.app13

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Appendix XIII: Tumor Associated Mutations in JAK2

David J. Matthews¹,

Mary E. Gerritsen²

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2016

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Cooperation of germ line JAK2 mutations E846D and R1063H in hereditary erythrocytosis with megakaryocytic atypia

Kapralova

Horváthová

Pecquet

et al. 2016

Blood

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• Cells expressing JAK2 E846D or R1063H exhibit pathologic STAT5 activation in the specific context of EPOR.• Cooperation of germ line JAK2 mutations E846D and R1063H defines a JAK2-signaling threshold for induction of erythrocytosis.The role of somatic JAK2 mutations in clonal myeloproliferative neoplasms (MPNs) is well established. Recently, germ line JAK2 mutations were associated with polyclonal hereditary thrombocytosis and triple-negative MPNs. We studied a patient who inherited 2 heterozygous JAK2 mutations, E846D from the mother and R1063H from the father, and exhibited erythrocytosis and megakaryocytic atypia but normal platelet number. Culture of erythroid progenitors from the patient and his parents revealed hypersensitivity to erythropoietin (EPO). Using cellular models, we show that both E846D and R1063H variants lead to constitutive signaling (albeit much weaker than JAK2 V617F), and both weakly hyperactivate JAK2/STAT5 signaling only in the specific context of the EPO receptor (EPOR). JAK2 E846D exhibited slightly stronger effects than JAK2 R1063H and caused prolonged EPO-induced phosphorylation of JAK2/STAT5 via EPOR. We propose that JAK2 E846D predominantly contributes to erythrocytosis, but is not sufficient for the full pathological phenotype to develop. JAK2 R1063H, with very weak effect on JAK2/ STAT5 signaling, is necessary to augment JAK2 activity caused by E846D above a threshold level leading to erythrocytosis with megakaryocyte abnormalities. Both mutations were detected in the germ line of rare polycythemia vera, as well as certain leukemia patients, suggesting that they might predispose to hematological malignancy.

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Cooperation of germ line JAK2 mutations E846D and R1063H in hereditary erythrocytosis with megakaryocytic atypia

Kapralova

Horváthová

Pecquet

et al. 2016

Blood

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Appendix XIII: Tumor Associated Mutations in JAK2

Cited by 1 publication

References 8 publications

Cooperation of germ line JAK2 mutations E846D and R1063H in hereditary erythrocytosis with megakaryocytic atypia

Cooperation of germ line JAK2 mutations E846D and R1063H in hereditary erythrocytosis with megakaryocytic atypia

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