The Prognostic Significance of Gene Mutations in Myeloproliferative Neoplasms

Relevant gene mutations in MPN and their prognostic significance for primary myelofibrosis (PMF).

Myeloproliferative neoplasms (MPN) are a group of blood cancers characterized by significant symptoms and a high risk of transformation into acute leukemia. MPN include (primary) myelofibrosis (PMF), essential thrombocythemia (ET) and polycythemia vera (PV), and affect around 13,000, 134,000 and 148,000 patients in the US, respectively (1). The rarity of MPNs is further reflected in a 2014 global random effects meta-analysis study which reported combined annual incidence rates for PMF, ET and PV of 0.47, 1.03 and 0.84 per 100,000, respectively (2). Myelofibrosis is a type of MPN that is usually caused by one of three genetic mutations within the JAK2 signaling pathway (3). Earlier this year, updated clinical guidelines for MPN were included in the update to the WHO guidelines for the classification of myeloid neoplasms and acute leukemia (4; see related post here). In addition, new guidelines for MPN were recently published, which focus on diagnosis, treatment and supportive care strategies for myelofibrosis (16).  Below is a summary of relevant gene mutations in MPN and their prognostic significance for PMF.

JAK2 V617F is an indicator of intermediate prognosis and higher risk of thrombosis compared to patients with CALR mutations (5).

CALR mutations indicate improved survival (5–8) compared to patients with JAK2 mutation and ‘triple-negative’ PMF, and lower risk of thrombosis compared to patients with JAK2 mutation (5).

CALR Type 1/Type 1-like mutations indicate improved overall survival compared to CALR Type 2/Type2-like and the JAK2 V617F mutation (9–12).

MPLW515L/K mutations indicate higher risk of thrombosis and intermediate prognosis compared to patients with CALR mutations (5).

“Triple-negative” (non-mutated JAK2, MPL and CALR) indicate inferior leukemia-free survival compared to patients with JAK2- and/or CALR-mutated PMF (5–7), and inferior overall survival compared to patients with CALR-mutated PMF (6).

ASXL1 mutations and SRSF2 mutations are each separately and independently associated with inferior leukemia-free survival and inferior overall survival (13).

Combined CALR and ASXL1 mutation status: Survival is expected to be the longest for CALR(+)ASXL1(-) patients (median 10.4 years) and the shortest in CALR(-)ASXL1(+) patients (median 2.3 years) (14), while intermediate survival (median 5.8 years) is expected for CALR(+)ASXL1(+) or CALR(-)ASXL1(-) patients (14).

IDH1/IDH2 mutations are independently associated with inferior leukemia-free survival (13).

EZH2 mutations are independently associated with inferior overall survival (13).

TP53 mutations are associated with leukemic transformation (15).

QIAGEN’s ipsogen portfolio offers an expanding menu of reliable solutions for improved translational research and molecular diagnostics for hematological cancers such as MPN. For specific diagnosis of myeloproliferative neoplasms (MPN) the ipsogen_JAK2_RGQ_PCR_Kit* can be used for quick and precise quantification of the JAK2 V617F mutation. For CALR testing, the ipsogen CALR RGQ PCR Kit will soon be available in CE-IVD and can be used in the same workflow as the CE-IVD ipsogen JAK2 RGQ PCR kit for detection of both JAK2 V617F and CALR exon 9 mutations from the same blood sample. The CALR_RGQ_PCR_Kit** will soon be available in the US for research use only. For sensitive, qualitative detection of MPLW515L/K mutations for hematological cancer research, the ipsogen_MPL_W515L/K_MutaScreen_Kit ** offers an easy workflow and reliable, reproducible results.

QIAGEN also offers the next-generation sequencing (NGS) QIAseq_Targeted_Panel† solution, which is NGS platform-agnostic for digital DNA sequencing, and utilizes molecular barcodes to detect variants with high confidence. The Human Myeloid Neoplasms QIASeq DNA Panel† enables NGS analysis of the 141 genes most commonly mutated in myeloid neoplasm samples and involved in development and progression of these cancers, including those summarized above. For a complete gene list, see here.

Find out more about the broad ipsogen portfolio of oncohematology biomarker solutions available for research use only in the US and products available in Europe.

* Available for in vitro diagnostic (IVD) use in Europe; available in a research use only version in the US.

** For research use only. Not for use in diagnostics procedures. No claim or representation is intended to provide information for the diagnosis, prevention, or treatment of a disease.

† QIAseq Targeted DNA Panels are intended for molecular biology applications. These products are not intended for the diagnosis, prevention, or treatment of a disease.



  1. 1. Metha, J., et al. (2014) Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymph 55:595–600. Link
  2. 2. Titmarsh, G.J., et al. (2014) How common are myeloproliferative neoplasms? A systematic review and meta-analysis. Am. J. Hematol 89(6):581–7. Link
  3. 3. Kralovics. R., et al. (2005) A gain-of-function mutation of JAK2 in myeloproliferative disorders. NEJM. 352:1779–90. Link
  4. 4. Arber, D.A., et al. (2016) The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127:2391–2405.Link
  5. 5. Rumi, E., et al. (2014) Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood 124: 1062–1069. Link
  6. 6. Tefferi, A., et al. (2014) CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia 28: 1472–1477. Link
  7. 7. Tefferi, A., et al. (2014) Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood 124: 2507–2513. Link
  8. 8. Klampfl, T., et al. (2013) Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms. N Engl J Med 369: 2379–2390. Link
  9. 9. Guglielmelli, P., et al. (2015) Validation of the differential prognostic impact of type 1/type 1-like versus type 2/type 2-like CALR mutations in myelofibrosis. Blood Cancer J 5: e360. Link
  10. 10. Tefferi, A. et al. (2014) The prognostic advantage of calreticulin mutations in myelofibrosis might be confined to type 1 or type 1-like CALR variants. Blood 124: 2465–2466. Link
  11. 11. Tefferi, A., et al. (2014) Type 1 vs type 2 calreticulin mutations in primary myelofibrosis: differences in phenotype and prognostic impact. Leukemia 28: 1568–1570. Link
  12. 12. Li, B., et al. (2014) Calreticulin mutations in Chinese with primary myelofibrosis. Haematologica 99:1697–1700. Link
  13. 13. Vannucchi, A.M., et al. (2013) Mutations and prognosis in primary myelofibrosis. Leukemia 27:1861–1869. Link
  14. 14. Tefferi, A. et al. (2014). CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. Leukemia 28: 1494–1500. Link
  15. 15. Rampal, R., et al. (2014) Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proc Natl Adac Sci USA 111: E5401–5410. Link
  16. 16. Press Release, Posted on September 27, 2016 by MPN Advocacy & Education. Link




Kathryn Collinet

Kathryn Collinet, PhD, is a Technical and Marketing Writer for Personalized Healthcare and Oncology at QIAGEN. She trained as a molecular biologist at the University of Barcelona and the Institute for Research in Biomedicine, where she studied DNA and protein modifications and their influence on chromatin conformation and gene expression. Since 2011 Kathryn has been working in marketing communications for the scientific information and molecular diagnostics industries. Kathryn has a passion for delivering knowledge and insights about molecular and clinical technologies, and their power to impact research and healthcare.

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