Homozygosity of the JAK2 46/1 or GGCC Haplotype Contributes to Phenotype and Outcome Diversity Among Patients with Polycythemia Vera

• Published in: Blood 2024-11, Vol.144, p.1795-1795
• Main Authors: Guglielmelli, Paola, Maccari, Chiara, Balliu, Manjola, Loscocco, Giuseppe Gaetano, Gangat, Naseema, Atanasio, Alessandro, Cicogna, Paolo, Signori, Leonardo, Rotunno, Giada, Bartalucci, Niccolò, Nanni, Gloria, Catelani, Anna, Manfredini, Rossella, Paoli, Chiara, Tefferi, Ayalew, Vannucchi, Alessandro Maria
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-198891

Background: The JAK2 46/1, also referred to as the GGCC, haplotype, is represented by 4 main SNPs spanning a region of 250kb in chr9 including the JAK2 gene, that are in complete linkage disequilibrium. The GGCC haplo was found to confer susceptibility to JAK2 mutated myeloproliferative neoplasms (MPN) (Jones AV, 2009; Olcaydu D, 2009; Kilpivaara O, 2009) while association with JAK2-wildtype MPN remains controversial (Pardanani A, 2010; Jones AV, 2010; Guglielmelli P, 2010; Trifa A, 2016). The GGCC haplo was also found enriched in MPN pts with splancnic vein thrombosis (SVT) (Smalberg JH, 2011), and to correlate with higher JAK2V617F variant allele frequency (VAF) (Alvarez-Larran, A, 2012). Nullizigosity for GGCC haplo was associated with reduced survival (OS) in pts with myelofibrosis (MF) (Tefferi A, 2019), but no information on the impact of GGCC haplo status with phenotype and outcome in PV is available. Aim: To assess the clinical correlates and the prognostic significance of GGCC haplo status in a large cohort of pts with PV. Pts and Methods: A total of 399 PV pts, all JAK2V617F mutated, diagnosis revised according to 2022 ICC criteria, were genotyped for 46/1 haplotype by PCR allele discrimination with rs12343867 (with the “C” allele standing for 46/1 haplotype). Results: A total of 301 pts (75.4%) had the C allele, of which 143 (47.5%) were CC homo and 158 (52.5%) CT hetero; 98 (24.6%) were nullizygous for GGCC (TT). Since preliminary analysis disclosed no significant difference between CT and TT haplotype for all variables considered, homozygous CC pts were compared to TT+CT. The CC haplotype was associated with higher leukocytes (median 11.3x10e9/L vs 9.6, p