Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms

Abstract

In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P < .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positive predictive value for ring sideroblasts of 97.7% (95% confidence interval, 93.5%-99.5%). In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049). The close association between SF3B1 mutations and disease phenotype with ring sideroblasts across MDS and MDS/MPN is consistent with a causal relationship. Furthermore, SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS.

High frequencies of SF3B1 and JAK2 mutations in refractory anemia with ring sideroblasts associated with marked thrombocytosis strengthen the assignment to the category of myelodysplastic/myeloproliferative neoplasms

“…12 The only study of hematologic parameters in dependence of SF3B1mut in RARS-T patients detected no difference between SF3B1mut and SF3B1wt. 2 Our results confirmed this finding except that SF3B1mut cases had a significantly higher percentage of ring sideroblasts. This is comparable to results seen in MDS patients.…”

“…1 Remarkably, mutations in SF3B1 (splicing factor 3b, subunit 1) were associated with the morphological feature of ring sideroblasts 1-3 and were also found in refractory anemia with ring sideroblasts and marked thrombocytosis (RARS-T). 2,[4][5][6] This malignancy has been assigned as a provisional entity in the chapter "Myelodyplastic/myeloproliferative neoplasms, unclassifiable" of the WHO classification. 7 Patients have anemia, clinical and morphological features of myelodysplastic syndromes (MDS), but also show marked thrombocytosis associated with abnormal megakaryocytes resembling BCR-ABL1 negative myeloproliferative neoplasms (MPN).…”

“…This is comparable to results seen in MDS patients. 2 There is still ongoing discussion as to whether RARS-T is a distinct entity, or a subset of essential thrombocythemia or a progression of RARS. 7,8 In contrast to MDS, almost no SF3B1mut were found in MPN patients, 1,13 whereas JAK2V617F is characteristic for MPN and rare in MDS.…”

Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies

“…In MDS, SF3B1 mutations cluster with the presence of ring sideroblasts 3 and might be associated with better prognosis, although other investigators have questioned the histopathology-independent prognostic effect of the mutation in MDS. [22][23][24][25] In CLL, SF3B1 mutations were associated with deletions of chromosomal region 11q22 and ATM mutations (ATM is located at chromosome 11q22), as well as poor prognosis and resistance to fludarabine therapy. 4,6,26 OTHER SPLICEOSOME MUTATIONS In MDS, eight genes encoding proteins involved in RNA splicing are mutated with a variable frequency.…”

“…44 It is intriguing that several steps of the biology of RNA maturation, transport, translation and degradation appear to be targeted in the processes of malignant transformation (Figure 1). 26 7.5% (27/360) Quesada et al 6 9.7% (27/279) Wang et al 4 15% (14/91) SF3B1 in MDS Papaemmanuil et al 3 20.3% (72/354) Patnaik et al 23 49.5% (53/107) RS patients only Damm et al 22 14.7% (47/317) Malcovati et al 25 28 3 4.7% (5/106) Malcovati et al 25 6.5% (4/67) SF3B1 in Myelofibrosis Lasho et al 71 6.5% (19/155) Leukemia 2011 Papaemmanuil et al 3 4.4% (6/136) SF3B1 in AML Malcovati et al 25 5.3% (2/38) sAML only Yoshida et al 1 3.2% (7/213) Papaemmanuil et al 3 5.3% (3/57)…”