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The novel co-occurrence of JAK2, CALR & MPL mutations in a patient with myelofibrosis challenges previous knowledge that driver mutations cannot coexist.

Primary myelofibrosis (PMF) is the most advanced subtype of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). The majority of patients with PMF have mutually exclusive somatic driver mutations in one of three genes: JAK2 (60%-65%), CALR (20%-25%), or MPL (5%). Identifying driver mutations using next-generation sequencing (NGS) has diagnostic, prognostic, and therapeutic implications in MPNs.

However, cases of co-mutations are rare. Given that the limited data, clinical characteristics, and outcomes for patients with concurrent driver mutations have not been fully investigated, and their clinical relevance is unknown, researchers described a case report of a patient with all three driver mutations and discussed the possible underlying mechanisms. The findings were published in Hematology.

Details of Case Report

The patient was a 69-year-old man admitted to the hospital for acute exacerbation of COPD and was found to have splenomegaly and leukocytosis. NGS identified JAK2, CALR, and MPL  and additional variants in SF3B1, SRSF2, and STAG2. The patient was diagnosed with PMF and treated with a JAK2 inhibitor and COPD therapy. Because of nausea, physicians reduced the JAK2 inhibitor dose. After 6 months of targeted therapy, spleen volume decreased and hematologic responses were poor. The care team later identified another genetic mutation of ASXL1. The patient’s condition improved after medication adjustment and the addition of antiemetics.

This case report provides evidence that all three genes can coexist and challenges the assumption of their mutual exclusivity. Based on previous reports, mutations in JAK2, CAL, or MPL are sufficient to create an MPN phenotype, where each mutation can cause the distinctive characteristics of MPN. Furthermore, detrimental nondriver mutations, particularly high molecular risk mutations, are linked with high-risk clinical features, specific disease subtypes, shorter survival, and poor prognosis.

“This is a rare case report describing the coexistence of JAK2, CALR, and MPL driver mutations in PMF. This case demonstrates that three clone mutations are not mutually exclusive,” the researcher concluded. “However, due to a limited number of reports, it is unclear how co-occurrence of driver gene mutations affects MPN progression and prognosis. Larger-scale studies are necessary to confirm the possible pathogenetic mechanisms of these coexisting mutations and their potential biological significance.”