Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

U2AF1 mutations in primary myelofibrosis are strongly associated with anemia and thrombocytopenia despite clustering with JAK2V617F and normal karyotype

Leukemia volume 28, pages 431–433 (2014)Cite this article

Subjects

Spliceosome pathway mutations, including SF3B1, SRSF2, U2AF1(U2AF35) and ZRSR2, are recurrent in myeloid malignancies;1 the highest reported frequencies were 85% for myelodysplastic syndromes associated with ring sideroblasts (MDS-RS), 44% for MDS without RS and 55% for chronic myelomonocytic leukemia (CMML). SF3B1 mutations were the most frequent (75%) in MDS-RS and SRSF2 mutations in CMML (28%); U2AF1 mutational frequencies were 12% in MDS without RS and 8% in CMML.1 We have previously described SRSF22 and SF3B13 mutations in ∼ 17% and 6.5% of patients with primary myelofibrosis (PMF), respectively, and showed prognostic relevance for the former but not the latter. The objectives of the current study were to describe the incidence and phenotypic and prognostic relevance of U2AF1 mutations in PMF. Study patients were selected based on World Health Organization diagnosis of PMF4 and availability of bone marrow or granulocyte DNA for mutation screening. Mutational frequency, phenotypic correlation and prognostic relevance were assessed at time of referral. Risk stratification was according to the Dynamic International Prognostic Scoring System (DIPSS)-plus system.5 U2AF1 and other mutations were analyzed as per previous reports.6, 7

A total of 250 PMF patients (median age 63 years; 64% males) were studied (Table 1). DIPSS-plus risk distribution was high in 80 (32%), intermediate-2 in 94 (38%), intermediate-1 in 43 (17%) and low in 33 (13%) patients. Prevalence of additional clinical features at time of referral are listed in Table 1: 42% for age >65 years, 32% for transfusion need, 47% for hemoglobin <10 g/dl, 16% for leukocyte count >25 × 10(9)/l, 21% for platelet count <100 × 10(9)/l, 57% for ⩾1% blasts and 34% for constitutional symptoms. Cytogenetic studies were available in 247 patients and included normal karyotype in 63%, favorable abnormalities in 28% and unfavorable abnormalities in 9%.8 Other mutations that were concomitantly analyzed with U2AF1 mutations included SRSF2, SF3B1, ASXL1, EZH2, IDH1, IDH2, JAK2 and MPL and were selected because of their phenotypic or prognostic relevance in PMF.7, 9

Table 1 Clinical and laboratory features of 250 patients with primary myelofibrosis, stratified by the presence or absence of U2AF1 mutations
Full size table

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011; 478: 64–69.

    Article  CAS  Google Scholar 

  2. Lasho TL, Jimma T, Finke CM, Patnaik M, Hanson CA, Ketterling RP et al. SRSF2 mutations in primary myelofibrosis: significant clustering with IDH mutations and independent association with inferior overall and leukemia-free survival. Blood 2012; 120: 4168–4171.

    Article  CAS  Google Scholar 

  3. Lasho TL, Finke CM, Hanson CA, Jimma T, Knudson RA, Ketterling RP et al. SF3B1 mutations in primary myelofibrosis: clinical, histopathology and genetic correlates among 155 patients. Leukemia 2012; 26: 1135–1137.

    Article  CAS  Google Scholar 

  4. Tefferi A, Vardiman JW . Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008; 22: 14–22.

    Article  CAS  Google Scholar 

  5. Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol 2011; 29: 392–397.

    Article  Google Scholar 

  6. Patnaik MM, Padron E, Laborde RR, Lasho TL, Finke CM, Hanson CA et al. Mayo prognostic model for WHO-defined chronic myelomonocytic leukemia: ASXL1 and spliceosome component mutations and outcomes. Leukemia 2013; 27: 1504–1510.

    Article  CAS  Google Scholar 

  7. Vannucchi AM, Lasho TL, Guglielmelli P, Biamonte F, Pardanani A, Pereira A et al. Mutations and prognosis in primary myelofibrosis. Leukemia 2013; 27: 1861–1869.

    Article  CAS  Google Scholar 

  8. Caramazza D, Begna KH, Gangat N, Vaidya R, Siragusa S, Van Dyke DL et al. Refined cytogenetic-risk categorization for overall and leukemia-free survival in primary myelofibrosis: a single center study of 433 patients. Leukemia 2011; 25: 82–88.

    Article  CAS  Google Scholar 

  9. Tefferi A, Jimma T, Sulai NH, Lasho TL, Finke CM, Knudson RA et al. IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: clinical evidence for leukemogenic collaboration with JAK2V617F. Leukemia 2012; 26: 475–480.

    Article  CAS  Google Scholar 

  10. Graubert TA, Shen D, Ding L, Okeyo-Owuor T, Lunn CL, Shao J et al. Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat. Genet 2012; 44: 53–57.

    Article  CAS  Google Scholar 

  11. Przychodzen B, Jerez A, Guinta K, Sekeres MA, Padgett R, Maciejewski JP et al. Patterns of missplicing due to somatic U2AF1 mutations in myeloid neoplasms. Blood 2013; 122: 999–1006.

    Article  CAS  Google Scholar 

  12. Patnaik MM, Lasho TL, Finke CM, Hanson CA, Hodnefield JM, Knudson RA et al. Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: prevalence, clinical correlates, and prognostic relevance. Am J Hematol 2013; 88: 201–206.

    Article  CAS  Google Scholar 

  13. Wu SJ, Tang JL, Lin CT, Kuo YY, Li LY, Tseng MH et al. Clinical implications of U2AF1 mutation in patients with myelodysplastic syndrome and its stability during disease progression. Am J Hematol 2013; (in press).

  14. Thol F, Kade S, Schlarmann C, Loffeld P, Morgan M, Krauter J et al. Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. Blood 2012; 119: 3578–3584.

    Article  CAS  Google Scholar 

  15. Damm F, Kosmider O, Gelsi-Boyer V, Renneville A, Carbuccia N, Hidalgo-Curtis C et al. Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes. Blood 2012; 119: 3211–3218.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    A Tefferi, C M Finke, T L Lasho, E A Wassie & A Pardanani

  2. Division of Cytogenetics, Mayo Clinic, Rochester, MN, USA

    R Knudson & R P Ketterling

  3. Division of Hematopathology, Mayo Clinic, Rochester, MN, USA

    C A Hanson

Authors
  1. A Tefferi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C M Finke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T L Lasho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E A Wassie
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R Knudson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R P Ketterling
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C A Hanson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Pardanani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Tefferi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tefferi, A., Finke, C., Lasho, T. et al. U2AF1 mutations in primary myelofibrosis are strongly associated with anemia and thrombocytopenia despite clustering with JAK2V617F and normal karyotype. Leukemia 28, 431–433 (2014). https://doi.org/10.1038/leu.2013.286

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2013.286

This article is cited by

Search

Advanced search

Quick links