Concomitant and noncanonical JAK2 and MPL mutations in JAK2V617F‐ and MPLW515 L‐positive myelofibrosis

Abstract

Sequential genotyping for phenotype-driver mutations in JAK2 (exon 14), CALR (exon 9), and MPL (exon 10) is recommended in patients with myeloproliferative neoplasms. Yet, atypical JAK2-and MPL-mutations were described in some triple-negative patients. Whether noncanonical and/or concomitant JAK2-and MPL-mutations exist in myelofibrosis (MF) regardless of phenotype-driver mutations is not yet elucidated. For this, next-generation sequencing (NGS) was performed using blood genomic DNA from 128 MF patients (primary MF, n = 93; post-ET-MF, n = 18; post-PV-MF, n = 17). While no atypical JAK2-or MPL-mutations were seen in 24 CALR-positive samples, two JAK2-mutations [c.3323A > G, p.N1108S; c.3188G > A, p.R1063H] were detected in two of the 21 (9.5%) triple-negative patients. Twelve of the 82 (14.6%) JAK2V617Fpositive cases had coexisting germline JAK2-mutations [JAK2R1063H, n = 6; JAK2R893T, n = 1; JAK2T525A, n = 1] or at least one somatic MPL-mutation [MPLY591D, n = 3; MPLW515 L, n = 2; MPLE335K, n = 1]. Overall, MPL-mutations always coexisted with JAK2V617F and/or other MPL-mutations. None of the JAK2V617F plus a second JAK2-mutation carried a TET2-mutation but all patients with JAK2V617F plus an MPL-mutation harbored a somatic TET2-mutation. Four genomic clusters could be identified in the JAK2V617F-positive cohort. Cluster-I (10%) (noncanonical JAK2 mutated (mut) + TET2 wildtype (wt) ) were younger and had less proliferative disease compared with cluster-IV (5%) (TET2 mut + MPL mut ). In conclusion, recurrent concomitant classical and/or noncanonical JAK2-and MPL-mutations could be detected by NGS in 15.7% of JAK2V617F-and MPLW515-positive MF patients with genotype-phenotype associations. Many of the germline and/or somatic mutations might act as "Significantly Mutated Genes" contributing to the pathogenesis and phenotypic heterogeneity. A cost-effective NGS-based approach might be an important step towards patient-tailored medicine. K E Y W O R D S germline mutations, JAK2 mutation, MPL mutation, myelofibrosis, noncanonical mutations, somatic mutations

Clinical laboratory characteristics and gene mutation spectrum of Ph‐negative MPN patients with atypical variants of JAK2, MPL, or CALR

“…In Western research on atypical variants of driver genes in Ph ‐negative MPN patients, the most common is JAK2 R1063H . 25 , 26 However, in our study JAK2 R1063H was not found, which is speculated to be due to differences in population genetic background. The JAK2 R1063H is a germline variation and is an SNP (rs41316003).…”

“…Schulze et al. 25 found that 15% (12/82) of JAK2 V617F positive patients also carry atypical variants in JAK2 or classical mutations/atypical variants in MPL , but did not discover classical mutations or atypical variants in JAK2 or MPL in patients positive for the classical mutation in CALR Exon9 . In our study, 16% (45/288) of JAK2 V617F positive patients carry atypical variants in JAK2 , MPL , or CALR .…”

Genetic and Clinical Characteristics of Patients with Philadelphia-Negative Myeloproliferative Neoplasm Carrying Concurrent Mutations in JAK2V617F, CALR, and MPL

“…In this study, we searched the PubMed database and screened 23 articles (Supplementary Table). 14–36 As a result, 119 patients with MPN were found to display concurrent mutations in MPN driver genes, of which 97 had ET (81.51%, 97/119), 17 had PMF (14.29%, 17/119), 1 had PV (0.84%, 1/119), and 4 had U-MPN (3.36%, 4/119). The mutation combinations included JAK2V617F and CALR (77.31%, 92/119), JAK2V617F and MPL (18.49%, 22/119), and CALR with MPL (4.20%, 5/119).…”

Elevated erythroferrone distinguishes erythrocytosis with inherited defects in oxygen‐sensing pathway from primary familial and congenital polycythaemia

“…Similarly to EPOR gain-of-function mutations, predisposing potential of germline variants JAK2 E846D , JAK2 N1108S and JAK2 G571S for the development of myeloid or lymphoid malignancies was proposed. 4,5,34,55 Although existing data suggest that these weakly activating JAK2 germline variants belong to low-penetrance variants, this aspect of the slightly increased risk of developing haematological malignancy warrants long-term follow-ups of these patients.…”

“…The possible JAK2 cooperating genetic lesions contributing to erythrocytosis and detected in our patients are represented by PIEZO1 R1925W in P16 and TET2 A1443V in P18, but this cooperation needs to be established by systematic in vitro and in vivo experiments. Similarly to EPOR gain‐of‐function mutations, predisposing potential of germline variants JAK2 E846D , JAK2 N1108S and JAK2 G571S for the development of myeloid or lymphoid malignancies was proposed 4,5,34,55 . Although existing data suggest that these weakly activating JAK2 germline variants belong to low‐penetrance variants, this aspect of the slightly increased risk of developing haematological malignancy warrants long‐term follow‐ups of these patients.…”