A Hidden Driver Mutation in Myeloproliferative Neoplasms: SH2B3 and Diagnostic Implications and Response to Ropeginterferon Alfa-2b

Myeloproliferative neoplasms (MPNs) are commonly linked to driver mutations in the JAK2, MPL, and CALR genes. In contrast, SH2B3 (LNK) mutations are uncommon and remain an under-characterized contributor to dysregulated JAK-STAT signaling. The clinical features and treatment responsiveness of SH2B3-mutated MPNs are not well defined, and data on outcomes with ropeginterferon alfa-2b in this molecular subgroup are limited. We report a 75-year-old man who presented for evaluation of headache, generalized bone pain, and night sweats and was found to have abnormal blood counts including persistent leukocytosis, erythrocytosis, and thrombocytosis. Prior molecular testing was negative for JAK2, MPL, and CALR mutations. Bone marrow examination showed hypercellularity with panmyelosis, mild megakaryocytic atypia, and WHO grade 1 reticulin fibrosis. Hematologic next-generation sequencing identified a pathogenic SH2B3 c.1481C>G (p.Ser494*) nonsense mutation, predicted to result in a loss of SH2B3’s C-terminal regulatory domain. Given the tri-lineage cytoses and marrow findings, a diagnosis of SH2B3-mutated MPN was established. He was started on ropeginterferon alfa-2b, resulting in resolution of his symptoms and complete hematologic response (WBC ≤ 10 × 10 ³ /μL, Hct ≤ 45%, and PLT ≤ 400 × 10 ³ /μL) within 12 weeks, without the need for phlebotomy or treatment-limiting adverse effects. This case underscores the clinical significance of SH2B3 mutations as a driver of triple-negative MPNs and supports their inclusion in molecular evaluation when classical mutations are absent. The favorable clinical and hematologic response to ropeginterferon alfa-2b suggests that interferon-based therapy may be effective in SH2B3-mutated MPNs.