A novel germline hyperactivating JAK2 mutation L604F

• DOI: 10.1007/s00277-023-05423-y
• Publication Date: 2023-08-28T06:02:00Z
• Authors: Lukáš Dvořáček; Jana Marková; Aleš Holoubek; Dana Grebeňová; David Kundrát; Kateřina Kuželová; Jiří Schwarz
• Keywords: Hematology

Somatic JAK2 mutations are the main molecular cause of vast majority polycythemia vera (PV) cases. According to a recent structural model, prevalent acquired V617F mutation improves stability dimer, thereby enhancing constitutive kinase activity. Germline usually do not largely alter signaling, although they may modulate impact V617F. We found an unusual germline L604F in homozygous form young PV patient, along with low allele burden mutation, and her apparently healthy sister. Their father PV-like disease had heterozygous state, without The functional consequences L604Fmutation were compared those induced by two different vitro model systems: (i) HEK293T cells transfected plasmids for exogenous JAK2-GFP expression, (ii) endogenous modifications introduced into HeLa using CRISPR/Cas9. Both significantly increased activity cells. In second modification resulted reduced total protein levels. An important difference was also detected: as described previously, effect on abrogated absence aromatic residue F595. contrast, hyperactivation only partially inhibited F595 change alanine. propose that increases probability spontaneous dimer formation, which is physiologically mediated addition, contribute stabilization similarly