SRSF2 mutation is present in the hypercellular and prefibrotic stage of primary myelofibrosis

To the editor:

Myeloproliferative neoplasms (MPNs) are characterized by their propensity to progress from overproduction of 1 or more hematopoietic lineages to states of cytopenia associated with myelofibrosis and/or blast excess. Recently, it was demonstrated that in progressed primary myelofibrosis (PMF) with cytopenia and higher dynamic international prognostic scoring system–plus risk category, 17% of patients exhibited a mutation of the spliceosome component SRSF2.¹  In myelodysplastic syndromes (MDSs), SRSF2 mutations are associated with inferior survival and progression to acute leukemia (AML).^2,3  It is not clear whether the transition from hypercellularity to cytopenia in MPN can be explained by fibrotic scarring of the bone marrow alone or whether this development is related to clonal evolution and acquisition of MDS-like mutations.⁴  To answer this question, we analyzed follow-up biopsies from 4 patients with PMF (according to the World Health Organization⁵ ), fully developed myelofibrosis, cytopenia, and SRSF2 mutation (Table 1). Previous biopsies that had been taken 2 to 5 years before were devoid of fibrosis. At that time, there had been no cytopenia but thrombocytosis (Table 1). In all 4 patients with SRSF2 mutation during the late stage, the abnormality was already present in the previous biopsy (Table 1). Parallel findings were reported in 53 MPN-derived AMLs.⁶  All 3 SRSF2-mutated AML cases with available pretransformation material exhibited the mutation already during the chronic phase.⁶ 

As described previously,¹  SRSF2 and IDH mutations appear to be associated. We found IDH2 mutation in 50% of patients in our small series (Table 1). Three out of 4 patients had the JAK2^V617F mutation. Interestingly, 1 patient has acquired the mutation after onset of disease (patient 4; Table 1). Reevaluation of histology and bone marrow smears did not show any correlate of SRSF2 mutation (eg, increased iron or MDS-like features in initial bone marrow trephines). At the time of the first biopsy, all patients fulfilled the criteria of prefibrotic PMF according to the World Health Organization including minor criteria.⁵ 

Because not all patients with prefibrotic PMF rapidly progress to end-stage disease and a subset of patients is hard to discriminate from low-risk essential thrombocytopenia (ET),⁷  SRSF2 mutation could provide a useful prognostic marker in the early stages of PMF. In a series of 80 MPNs with available follow-up biopsies (range 1-10 years, median 3 years) including 56 cases with nonprogressing ET, SRSF2 mutations (sequenced codons 93-102) occurred exclusively in prefibrotic PMF with progression to myelofibrosis (4/24), but not in ET (0/56).

Allelic burden of mutated SRSF2 has not been determined in MPN so far.¹  Because SRSF2 mutation is associated with pronounced thrombocytopenia in MDS,³  we hypothesized that transition from thrombocytosis to normal counts or thrombocytopenia in PMF might be caused by occurrence of SRSF2 mutation or increase of its allelic burden. Using quantitative pyrosequencing, we found 35% to 45% of alleles mutated in the initial and follow-up biopsy. With progression to fibrosis and reduction of thrombocyte counts, the allelic burden did not change significantly (Table 1). In PMF, SRSF2 mutation appears to be stable and not associated with progression from previous thrombocytosis to cytopenia. This study was approved by the Ethic Committee of Hannover Medical School.