Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Nov 30;1(2):105-111.
doi: 10.1182/bloodadvances.2016000208. eCollection 2016 Dec 13.

Targeted deep sequencing in primary myelofibrosis

Ayalew Tefferi  1 , Terra L Lasho  1 , Christy M Finke  1 , Yoseph Elala  1 , Curtis A Hanson  2 , Rhett P Ketterling  3 , Naseema Gangat  1 , Animesh Pardanani  1
Affiliations

Targeted deep sequencing in primary myelofibrosis

Ayalew Tefferi et al. Blood Adv. .

Abstract

A myeloid neoplasm-relevant 27-gene panel was used for next-generation sequencing of bone marrow or whole blood DNA in 182 patients with primary myelofibrosis (PMF). DNA sequence variants/mutations other than JAK2/CALR/MPL were detected in 147 patients (81%), with the most frequent being ASXL1 (36%), TET2 (18%), SRSF2 (18%), and U2AF1 (16%); furthermore, 35%, 26%, 10%, and 9% of the patients harbored 1, 2, 3, or 4 or more such variants/mutations, respectively. Adverse variants/mutations were identified by age-adjusted multivariable analysis of impact on overall survival or leukemia-free survival and included ASXL1, SRSF2, CBL, KIT, RUNX1, SH2B3, and CEBPA; their combined prevalence was 56%. Adverse variants/mutations were associated with inferior overall survival (median, 3.6 vs 8.5 years; P < .001) and leukemia-free survival (7-year risk, 25% vs 4%; P < .001), and the effect on survival was independent of both the Dynamic International Prognostic Scoring System Plus and JAK2/CALR/MPL mutational status, with respective hazard ratios of 2.0 (95% confidence interval [CI], 1.3-3.1) and 2.9 (95% CI, 1.9-4.4). Additional prognostic information was obtained by considering the number of adverse variants/mutations; median survivals in patients with zero (n = 80), 1 or 2 (n = 93), or 3 or more (n = 9) adverse variants/mutations were 8.5, 4, and 0.7 years, respectively (P < .001). Additional data were obtained on pattern of mutation co-segregation and phenotypic correlation, including significant associations between U2AF1 and JAK2 mutations (P = .04) and U2AF1 mutations and anemia (P = .003) and thrombocytopenia (P = .006). We conclude that DNA variants/mutations other than JAK2/CALR/MPL are prevalent in PMF and are qualitatively and quantitatively relevant in predicting overall and leukemia-free survival.

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Twenty-seven-gene panel DNA sequence variants in Mayo Clinic patients with PMF (n = 182). (A) Co-segregation plot for individual variants/mutations in PMF. Each column represents 1 patient. Variants/mutations are depicted by representative colored bars. Red: variants previously associated with a hematologic malignancy, identified as being somatic and present with ≤1% MAF; Pink: variants previously associated with a hematologic malignancy and present with ≤1% MAF; Blue: variants not previously associated with a hematologic malignancy and present with ≤1% MAF. (B) Total variants/mutations in PMF ranked by gene and corresponding overall frequency percentage.
Figure 2.
Figure 2.
Overall survival curves in 182 patients with PMF, stratified by the presence of adverse (ASXL1, SRSF2, CBL, KIT, RUNX1, SH2B3, and CEBPA) vs nonadverse variants/mutations vs no DNA sequence variants/mutations.
Figure 3.
Figure 3.
Overall survival curves in 182 patients with PMF, stratified by the number of adverse variants/mutations: 3 or more vs 1 or 2 vs no adverse variants/mutations.
See this image and copyright information in PMC

References

    1. Tefferi A, Pardanani A. Myeloproliferative Neoplasms: A Contemporary Review. JAMA Oncol. 2015;1(1):97-105. - PubMed
    1. Vainchenker W, Delhommeau F, Constantinescu SN, Bernard OA. New mutations and pathogenesis of myeloproliferative neoplasms. Blood. 2011;118(7):1723-1735. - PubMed
    1. Tefferi A, Guglielmelli P, Larson DR, et al. . Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood. 2014;124(16):2507-2513. - PMC - PubMed
    1. Tefferi A, Lasho TL, Schwager SM, et al. . The JAK2(V617F) tyrosine kinase mutation in myelofibrosis with myeloid metaplasia: lineage specificity and clinical correlates. Br J Haematol. 2005;131(3):320-328. - PubMed
    1. Vannucchi AM, Guglielmelli P. Molecular pathophysiology of Philadelphia-negative myeloproliferative disorders: beyond JAK2 and MPL mutations. Haematologica. 2008;93(7):972-976. - PubMed