JAK2 Variants Associated with Secondary-AML from MPN

Abstract Background Canonical JAK2 V617F and exon 12 mutations in myeloid neoplasms are well described. There are limited reports of other rare JAK2 variants of potential clinical relevance. We sought to survey JAK2 variants in a large cohort of MPN and AML patients and determine the likelihood of contribution to disease pathogenesis. Methods We retrospectively analyzed the JAK2 variant profile and mutational landscape of MPN and AML. Targeted, amplicon-based, next-generation sequencing of the coding region of JAK2 and 27 other leukemia-related genes was performed on DNA extracted from diagnostic bone marrow samples. The study population was classified into three cohorts: chronic myeloproliferative neoplasm-only (MPN); MPN transformed to AML (MPN>>AML); and AML-only, excluding MPN>>AML patients (AML). Results Of 3,376 MPN and AML patients, 2,154 patients underwent JAK2 sequencing. Non-V617F/non-exon 12 JAK2 sequence variants were identified in 114 (5.3%, Fig 1A). This included 35 unique JAK2 variants including several previously undescribed variants located within all functional domains (Fig 1B). Ten variants have been previously reported in cases of hematologic proliferation or shown to be activating alterations. Sixteen of 114 JAK2 variants occurred alone without somatic mutations in the remaining 27 somatic genes tested. JAK2 variants were detected at a significantly higher frequency in the MPN>>AML cohort (15.3%) compared with MPN (4.6%, p Conclusions Full exonic gene sequencing of JAK2 identified several JAK2 variants of potential clinical relevance. JAK2 variants may represent an important and potentially overlooked component of MPN/AML pathogenesis, evidenced by the prevalence of variants previously shown to have JAK2 activating effects, the frequencies of specific variants in MPN/AML compared to the general population, and the predicted functional effect of variant amino acid substitutions. Specific JAK2 variants detected in MPN patients may be meaningful predictors for transformation to AML. Download : Download high-res image (201KB) Download : Download full-size image Figure 1 . Disclosures DiNardo: Agios: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Bose: Incyte Corporation: Honoraria. Pemmaraju: affymetrix: Research Funding; LFB: Consultancy, Honoraria; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Honoraria; novartis: Consultancy, Honoraria, Research Funding; roche diagnostics: Consultancy, Honoraria; abbvie: Research Funding. Cortes: ARIAD: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Teva: Research Funding; Pfizer: Consultancy, Research Funding; Sun Pharma: Research Funding. Kantarjian: Amgen: Research Funding; Bristol-Meyers Squibb: Research Funding; Delta-Fly Pharma: Research Funding; Pfizer: Research Funding; ARIAD: Research Funding; Novartis: Research Funding. Verstovsek: Galena BioPharma: Research Funding; Lilly Oncology: Research Funding; Seattle Genetics: Research Funding; NS Pharma: Research Funding; CTI BioPharma Corp: Research Funding; Bristol Myers Squibb: Research Funding; Astrazeneca: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Lilly Oncology: Research Funding; Gilead: Research Funding; Galena BioPharma: Research Funding; Seattle Genetics: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Blueprint Medicines Corp: Research Funding; Roche: Research Funding; Astrazeneca: Research Funding; Bristol Myers Squibb: Research Funding; CTI BioPharma Corp: Research Funding; Incyte: Research Funding; Blueprint Medicines Corp: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Celgene: Research Funding; Promedior: Research Funding.