LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations.

LNK mutation analysis was performed in 61 patients with blast-phase myeloproliferative neoplasms (MPN); post-primary myelofibrosis (PMF) in 41, post-polycythemia vera in 11 and post-essential thrombocythemia in 9 patients. Paired chronic-blast phase sample analysis was possible in 26 cases. Nine novel heterozygous LNK mutations were identified in eight (13%) patients: six exon 2 missense mutations involving codons 215, 220, 223, 229 and 234, a synonymous mutation involving codon 208, and two deletion mutations involving exon 2 (685-691_delGGCCCCG) or exon 5 (955_delA); eight affected the pleckstrin homology (PH) domain. Mutations were detected in six (9.8%) blast-phase samples; chronic-phase sample analysis in four of these revealed the same mutation in one. Mutant LNK was detected in chronic-phase only in two patients and in both chronic-blast phases in one. JAK2V617F was documented in three and IDH2R140Q in one LNK-mutated patients. LNK mutations were not detected in 78 additional patients with chronic-phase MPN enriched for TET2, IDH, JAK2V617F, or MPL-mutated cases. We conclude that LNK mutations (i) target an exon 2 'hot spot' in the PH domain spanning residues E208-D234, (ii) might be more prevalent in blast-phase PMF and (iii) are not mutually exclusive of other MPN-associated mutations but rarely occur in their presence in chronic-phase disease.