SF3B1 mutations in primary myelofibrosis: clinical, histopathology and genetic correlates among 155 patients

Lasho, Terra L.; Finke, Christy; Hanson, Curtis A.; Jimma, Thitina; Knudson, Ryan A.; Ketterling, Rhett P.; Pardanani, Animesh; Tefferi, Ayalew

doi:10.1038/leu.2011.320

Cited by 106 publications

(81 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus far, in CMML loss of function gene mutations involving ASXL1 and EZH2 have been associated with poor outcome [10,11]. Recently, mutations involving the spliceosome machinery have been described in patients with myeloid neoplasms, including MDS, CMML, MPN, and AML [12,13,17,18,30]. Spliceosome aberrations have also been described in solid tumors, examples being recurrent somatic mutations of U2AF35 in adenocarcinoma of the lung [31], and overexpression of SRSF1 and SRSF2 in both adeno and squamous cell lung cancers [32].…”

Section: Discussionmentioning

confidence: 99%

“…Mutations involving SF3B1 are common in MDS-RS ( 80%), and to a lesser extent in PMF (<10%), but hold no independent prognostic value [12,17,25]. These mutations have a strong phenotypic correlation with the presence of BM RS.…”

Section: Discussionmentioning

confidence: 99%

“…RS are erythroid precursors with iron-laden mitochondria forming a perinuclear ring and are common in patients with myeloid neoplasms, including MDS, MPN, and MDS/MPN overlap syndromes [1,17,33]. The presence of 15% RS constitutes the operational diagnosis of MDS-RS [33].…”

Section: Discussionmentioning

confidence: 99%

“…SF3B1 mutations have a high prevalence ( 80%) in MDS and ring sideroblasts (RS) and do not influence either OS or leukemiafree survival (LFS) [15,16]. Similarly, these mutations are seen in a small fraction (<10%) of patients with primary myelofibrosis (PMF), are strongly associated with the presence of BM RS, but do not affect disease outcome [17]. SRSF2 mutations are seen in patients with MDS, CMML, MPN/PMF, and acute myeloid leukemia (AML) [12,13,16,[18][19][20], and are very rare in juvenile myelomonocytic leukemia [19,21].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: Prevalence, clinical correlates, and prognostic relevance

Patnaik¹,

Lasho²,

Finke³

et al. 2013

American J Hematol

141

View full text Add to dashboard Cite

SRSF2, SF3B1, and U2AF35 (U2AF1) are the three most frequent genes involved with spliceosome mutations in myeloid malignancies. SF3B1 mutations are most frequent (~80%) in myelodysplastic syndromes (MDS) with ring sideroblasts (RS) but lack prognostic relevance. SRSF2 mutations are associated with shortened overall (OS) and leukemia-free survival (LFS) in both MDS and myelofibrosis. In this study of 226 patients with chronic myelomonocytic leukemia (CMML), mutational frequencies were 40% for SRSF2 (all affecting P95), 6% for SF3B1 (primarily K700E) and 9% for U2AF35 (mostly S34F and Q157P/R). These mutations were mutually exclusive and 54% of the patients displayed at least one mutation. The three mutation groups were phenotypically similar, with the exception of higher RS% (P < 0.0001) in patients with SF3B1 mutations. At a median follow-up of 15 months, 176 (78%) deaths and 32 (14%) leukemic transformations were documented. OS (median survivals of 17, 16, 17, and 20 months; P 5 0.48) and LFS (leukemic transformation rates of 17, 13, 15, and 5%; P 5 0.63) were similar among patients with none of the three mutations, SRSF2, SF3B1, or U2AF35 mutations, respectively. We conclude that SRSF2 is the most frequently mutated spliceosome gene in CMML but neither it nor SF3B1 or U2AF35 mutations are prognostically relevant. Am. J. Hematol. 88:201-206, 2013. V C 2012 Wiley Periodicals, Inc. IntroductionChronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder characterized by features overlapping between myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). The 2008 World Health Organization (WHO) criteria for diagnosis of CMML include; persistent peripheral blood monocytosis >1 3 10(9)/L, absence of the BCR-ABL1 fusion, absence of rearrangements of the PDGFRA or PDGFRB genes, absence of 20% myeloblasts or promonocytes in the blood and bone marrow (BM), and presence of dysplasia in one or more myeloid lineages [1]. CMML is further subclassified into CMML-1 (<5% circulating blasts and <10% BM blasts) and CMML-2 (5-19% circulating blasts, 10-19% BM blasts, or when Auer rods are present irrespective of the blast count), with the median over-all survival (OS) being 20 and 15 months respectively [1,2].Genetic aberrations are common in CMML and tend to involve different cellular targets and epigenetic regulatory pathways. These include mutations involving; RUNX1 . Thus far, in CMML, loss-of-function mutations involving EZH2 and ASXL1 have been associated with poor outcomes [10,11]. The data with regard to the other mutations needs further elucidation.Mutations in genes of the splicing machinery, such as SF3B1 (splicing factor 3B, subunit 1), SRSF2 (serine/arginine-rich splicing factor 2) and U2AF35, also known as U2AF1 (U2 small nuclear RNA auxiliary factor) are common in patients with myeloid malignancies [12][13][14]. SF3B1 mutations have a high prevalence ( 80%) in MDS and ring sideroblasts (RS) and do not influence either OS or leukemiafree survival (LFS) [15,16]. Similarly, these...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: Prevalence, clinical correlates, and prognostic relevance

Patnaik¹,

Lasho²,

Finke³

et al. 2013

American J Hematol

141

View full text Add to dashboard Cite

show abstract

“…15 In addition to the previously mentioned JAK2V617F, 7 PMF and the other BCR-ABL1-negative MPNs are characterized by many other somatic mutations, including MPL, TET2, ASXL1, CBL, IDH1, IDH2, IKZF1, LNK, EZH2, DNMT3A, CUX1, and SF3B1 mutations. [16][17][18][19] None of these mutations are MF-specific, and it is currently believed that these mutations constitute secondary events with poorly defined pathogenetic contribution. 16 Primary myelofibrosis is currently diagnosed according to WHO criteria, 20 whereas the International Working Group for Myeloproliferative Neoplasms Research and Treatment criteria are used to diagnose post-PV or post-ET MF.…”

mentioning

confidence: 99%

One Thousand Patients With Primary Myelofibrosis: The Mayo Clinic Experience

Tefferi

Lasho

Jimma

et al. 2012

Mayo Clinic Proceedings

208

133

View full text Add to dashboard Cite

Objective: To share our decades of experience with primary myelofibrosis and underscore the importance of outcomes research studies in designing clinical trials and interpreting their results. Patients and Methods: One thousand consecutive patients with primary myelofibrosis seen at Mayo Clinic between November 4, 1977, and September 1, 2011, were considered. The International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS-plus were applied for risk stratification. Separate analyses were included for patients seen at time of referral (Nϭ1000), at initial diagnosis (Nϭ340), and within or after 1 year of diagnosis (Nϭ660). Results: To date, 592 deaths and 68 leukemic transformations have been documented. Parameters at initial diagnosis vs time of referral included median age (66 vs 65 years), male sex (61% vs 62%), red cell transfusion need (24% vs 38%), hemoglobin level less than 10 g/dL (38% vs 54%), platelet count less than 100 ϫ 10 9 /L (18% vs 26%), leukocyte count more than 25 ϫ 10 9 /L (13% vs 16%), marked splenomegaly (21% vs 31%), constitutional symptoms (29% vs 34%), and abnormal karyotype (31% vs 41%). Mutational frequencies were 61% for JAK2V617F, 8% for MPLW515, and 4% for IDH1/2. DIPSS-plus risk distributions at time of referral were 10% low, 15% intermediate-1, 37% intermediate-2, and 37% high. The corresponding median survivals were 17.5, 7.8, 3.6, and 1.8 years vs 20.0, 14.3, 5.3, and 1.7 years for patients younger than 60 years of age. Compared with both DIPSS and IPSS, DIPSS-plus showed better discrimination among risk groups. Five-year leukemic transformation rates were 6% and 21% in low-and high-risk patients, respectively. Conclusion: The current document should serve as a valuable resource for patients and physicians and provides context for the design and interpretation of clinical trials.

show abstract

Molecular genetics of the myeloproliferative neoplasms

Beer¹

2016

The Genetic Basis of Haematological Cancers

View full text Add to dashboard Cite

SF3B1 mutations in primary myelofibrosis: clinical, histopathology and genetic correlates among 155 patients

Cited by 106 publications

References 9 publications

Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: Prevalence, clinical correlates, and prognostic relevance

Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: Prevalence, clinical correlates, and prognostic relevance

One Thousand Patients With Primary Myelofibrosis: The Mayo Clinic Experience

Molecular genetics of the myeloproliferative neoplasms

Contact Info

Product

Resources

About