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PubMed This is a summary of 25 peer-reviewed journal articles Updated
Hematology

The Genetics of ET: Understanding Your Mutations

At a Glance

Essential Thrombocythemia (ET) is primarily driven by acquired genetic mutations in the bone marrow, most commonly in the JAK2, CALR, or MPL genes. Knowing your specific mutation type is crucial because it helps doctors predict your risk for blood clots and guides your overall treatment plan.

While the high platelet count is the most visible sign of Essential Thrombocythemia (ET), the “why” behind those numbers lies deep in your genetics. ET is caused by specific genetic changes—mutations—that occur in the DNA of your blood-forming cells during your lifetime [1][2]. These mutations act like a broken “on-switch,” telling your bone marrow to keep churning out platelets even when your body doesn’t need them [2][3].

The Three Main “Driver” Mutations

Most people with ET (about 85-90%) will have one of three primary mutations. These are called “driver” mutations because they are the main force behind the disease’s behavior [4][5].

1. JAK2 V617F (The Most Common)

Found in about 50–60% of ET patients, this mutation occurs in the JAK2 gene [4].

  • The Mechanism: This gene normally controls how cells respond to growth signals. The mutation makes the JAK2 protein constantly active, causing a permanent “on” signal for cell production [6][7].
  • Disease Behavior: Patients with the JAK2 mutation often have higher hemoglobin (red blood cell) and white blood cell levels alongside their elevated platelets [8][9].
  • Clot Risk: This mutation is associated with a higher risk of both arterial and venous blood clots compared to other ET subtypes [10][11].

2. CALR (The CALR-Subtype)

Found in about 20–25% of patients, this mutation occurs in the calreticulin gene [4].

  • The Mechanism: The mutated CALR protein takes on an abnormal shape that allows it to “trick” the platelet receptor (MPL) into staying permanently active [12][13].
  • Disease Behavior: These patients typically have much higher platelet counts but lower red and white blood cell counts than those with JAK2 mutations [8][14].
  • Clot Risk: Interestingly, despite having higher absolute platelet numbers, CALR-mutated patients generally have a lower risk of blood clots and often experience better overall long-term survival [15][11].

3. MPL

Found in about 3–5% of patients, this is a mutation in the thrombopoietin receptor gene itself [4].

  • The Mechanism: The receptor on the surface of the cell is permanently activated on its own, completely bypassing the body’s normal regulatory system [16][17].
  • Disease Behavior: This mutation is less common and is sometimes associated with an increased risk of bone marrow scarring (fibrosis) over time [18][19].

What Does “Triple-Negative” Mean?

About 10–15% of people with ET are triple-negative (TN-ET), meaning their tests do not show JAK2, CALR, or MPL mutations [20][21].

If you are triple-negative:

  • Diagnosis: Your doctor will look even more closely at your bone marrow biopsy to firmly confirm the disease and rule out other causes of high platelets, like severe iron deficiency or chronic inflammation [5][16].
  • Potential Causes: Advanced testing like Next-Generation Sequencing (NGS) often reveals other, rarer “non-driver” mutations (such as TET2 or ASXL1) that prove the disease is clonal (cancerous) [21][22].
  • Prognosis: Many triple-negative patients have very stable disease behavior with a significantly lower risk of blood clots than those with the JAK2 mutation [23][24].

Summary of Genetic Subtypes

Mutation Prevalence Average Platelet Count Clot Risk
JAK2 50–60% Moderate to High Higher [10]
CALR 20–25% Very High Lower [15]
MPL 3–5% High Variable [19]
Triple-Negative 10–15% Variable Lower [23]

Note: These are general trends based on the genetics. Your individual health factors, such as age and blood pressure, also play a major role in your personal risk [25].

Common questions in this guide

What is the most common genetic mutation in Essential Thrombocythemia?
The most common mutation is JAK2 V617F, found in about 50 to 60 percent of people with Essential Thrombocythemia. This genetic change creates a permanent signal for cell production and is associated with a higher risk of developing blood clots.
How does a CALR mutation affect ET prognosis and clot risk?
People with a CALR mutation often have much higher platelet counts than those with other subtypes. However, despite these high numbers, they generally have a lower risk of blood clots and often experience better long-term survival.
What does it mean to have triple-negative ET?
Being triple-negative means your testing did not find the three standard driver mutations (JAK2, CALR, or MPL). Your doctor may use advanced testing like Next-Generation Sequencing to find other rarer mutations, though triple-negative patients often have very stable disease with lower clot risks.
Why is it important to know my specific ET mutation?
Your specific genetic mutation greatly influences your risk for cardiovascular events like blood clots. This information helps your hematologist determine how closely you need to be monitored and whether you need certain treatments, such as aspirin or cytoreductive therapy.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Based on my specific mutation, how often should my platelet levels and cardiovascular health be routinely monitored?
  2. 2.Does my specific mutation status change the type of aspirin or cytoreductive therapy you would recommend for me?
  3. 3.If I am triple-negative, what additional evidence or tests were used to confirm this is a clonal bone marrow disease?
  4. 4.Are there any 'non-driver' mutations on my Next-Generation Sequencing (NGS) report that I should be concerned about?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (25)
  1. 1

    Time for revival of the red blood cell count and red cell mass in the differential diagnosis between essential thrombocythemia and polycythemia vera?

    Hasselbalch HC

    Haematologica 2019; (104(11)):2119-2125 doi:10.3324/haematol.2019.229039.

    PMID: 31666340
  2. 2

    Ruxolitinib for essential thrombocythemia refractory to or intolerant of hydroxyurea: long-term phase 2 study results.

    Verstovsek S, Passamonti F, Rambaldi A, et al.

    Blood 2017; (130(15)):1768-1771 doi:10.1182/blood-2017-02-765032.

    PMID: 28827411
  3. 3

    Philadelphia-negative myeloproliferative neoplasms as disorders marked by cytokine modulation.

    Cacemiro MDC, Cominal JG, Tognon R, et al.

    Hematology, transfusion and cell therapy 2018; (40(2)):120-131 doi:10.1016/j.htct.2017.12.003.

    PMID: 30057985
  4. 4

    Hematological relevance of JAK2 V617F and calreticulin mutations in Tunisian patients with essential thrombocythemia.

    Abdelghani M, Hammami H, Zidi W, et al.

    Journal of clinical laboratory analysis 2022; (36(8)):e24522 doi:10.1002/jcla.24522.

    PMID: 35754115
  5. 5

    Thrombotic risk correlates with mutational status in true essential thrombocythemia.

    Bertozzi I, Peroni E, Coltro G, et al.

    European journal of clinical investigation 2016; (46(8)):683-9 doi:10.1111/eci.12647.

    PMID: 27271054
  6. 6

    JAK2 V617F hematopoietic clones are present several years prior to MPN diagnosis and follow different expansion kinetics.

    McKerrell T, Park N, Chi J, et al.

    Blood advances 2017; (1(14)):968-971 doi:10.1182/bloodadvances.2017007047.

    PMID: 29296738
  7. 7

    Murine Modeling of Myeloproliferative Neoplasms.

    Chen K, Shih AH

    Hematology/oncology clinics of North America 2021; (35(2)):253-265 doi:10.1016/j.hoc.2020.11.007.

    PMID: 33641867
  8. 8

    [Mutation of CALR Gene in Patients with Chronic Myeloproliferative Neoplasm and Its Clinical Significance].

    Tang Q, Zhang XW, Xia L, Jiang NK

    Zhongguo shi yan xue ye xue za zhi 2017; (25(1)):151-156 doi:10.7534/j.issn.1009-2137.2017.01.027.

    PMID: 28245393
  9. 9

    Impact of CALR and JAK2V617F Mutations on Clinical Course and Disease Outcomes in Essential Thrombocythemia: A Multicenter Retrospective Study in Turkish Patients.

    Narlı Özdemir Z, İpek Y, Patır P, et al.

    Turkish journal of haematology : official journal of Turkish Society of Haematology 2024; (41(1)):26-36 doi:10.4274/tjh.galenos.2024.2023.0430.

    PMID: 38433449
  10. 10

    Calreticulin Mutated Essential Thrombocythemia Presenting as Acute Coronary Syndrome.

    Nazha B, Garcia G, Kandov R, Odaimi M

    Case reports in hematology 2015; (2015()):161764 doi:10.1155/2015/161764.

    PMID: 26064712
  11. 11

    Essential thrombocythemia with CALR mutation and recurrent stroke: two case reports and literature review.

    Chen R, Shi X, Wang L, et al.

    Therapeutic advances in neurological disorders 2022; (15()):17562864221092093 doi:10.1177/17562864221092093.

    PMID: 35498365
  12. 12

    The risk of thrombosis in essential thrombocythemia is associated with the type of CALR mutation: A multicentre collaborative study.

    Pérez Encinas MM, Sobas M, Gómez-Casares MT, et al.

    European journal of haematology 2021; (106(3)):371-379 doi:10.1111/ejh.13561.

    PMID: 33275803
  13. 13

    Activation of the thrombopoietin receptor by mutant calreticulin in CALR-mutant myeloproliferative neoplasms.

    Araki M, Yang Y, Masubuchi N, et al.

    Blood 2016; (127(10)):1307-16 doi:10.1182/blood-2015-09-671172.

    PMID: 26817954
  14. 14

    [CALR gene mutation detection and clinical observation of 150 essential thrombocythemia patients].

    Zhang X, Zhou M, Chao H, et al.

    Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 2015; (36(5)):378-82 doi:10.3760/cma.j.issn.0253-2727.2015.05.005.

    PMID: 26031522
  15. 15

    Myeloproliferative Neoplasms: A Contemporary Review.

    Tefferi A, Pardanani A

    JAMA oncology 2015; (1(1)):97-105 doi:10.1001/jamaoncol.2015.89.

    PMID: 26182311
  16. 16

    Low-Risk Essential Thrombocythemia: A Comprehensive Review.

    Robinson AJ, Godfrey AL

    HemaSphere 2021; (5(2)):e521 doi:10.1097/HS9.0000000000000521.

    PMID: 33880431
  17. 17

    Primary myelofibrosis: 2017 update on diagnosis, risk-stratification, and management.

    Tefferi A

    American journal of hematology 2016; (91(12)):1262-1271 doi:10.1002/ajh.24592.

    PMID: 27870387
  18. 18

    MPL mutations and palpable splenomegaly are independent risk factors for fibrotic progression in essential thrombocythemia.

    Haider M, Elala YC, Gangat N, et al.

    Blood cancer journal 2016; (6(10)):e487 doi:10.1038/bcj.2016.98.

    PMID: 27768091
  19. 19

    [Search for mutations in patients with Philadelphia negative myeloproliferative neoplasms in a public hospital in Chile].

    Jaramillo I, Torres V, Leyton L, et al.

    Revista medica de Chile 2022; (150(7)):849-854 doi:10.4067/s0034-98872022000700849.

    PMID: 37906817
  20. 20

    Mutational profiling in suspected triple-negative essential thrombocythaemia using targeted next-generation sequencing in a real-world cohort.

    Michail O, McCallion P, McGimpsey J, et al.

    Journal of clinical pathology 2021; (74(12)):808-811 doi:10.1136/jclinpath-2020-206570.

    PMID: 33144355
  21. 21

    Lab tests for MPN.

    Moncada A, Pancrazzi A

    International review of cell and molecular biology 2022; (366()):187-220 doi:10.1016/bs.ircmb.2021.02.010.

    PMID: 35153004
  22. 22

    DNMT3A mutations occur early or late in patients with myeloproliferative neoplasms and mutation order influences phenotype.

    Nangalia J, Nice FL, Wedge DC, et al.

    Haematologica 2015; (100(11)):e438-42 doi:10.3324/haematol.2015.129510.

    PMID: 26250577
  23. 23

    Understanding triple negative myeloproliferative neoplasms: pathogenesis, clinical features, and management.

    Tharakan S, Mascarenhas J, Tremblay D

    Leukemia & lymphoma 2024; (65(2)):158-167 doi:10.1080/10428194.2023.2277674.

    PMID: 38033130
  24. 24

    Reduced Platelet Activation in Triple-Negative Essential Thrombocythemia Compared with JAK2V617F-Mutated Essential Thrombocythemia.

    Dong H, Chen J, Zhang J, et al.

    Clinical cancer research : an official journal of the American Association for Cancer Research 2024; (30(23)):5473-5482 doi:10.1158/1078-0432.CCR-24-1731.

    PMID: 39330983
  25. 25

    Comparison between thrombotic risk scores in essential thrombocythemia and survival implications.

    Santoro M, Accurso V, Mancuso S, et al.

    Hematological oncology 2019; (37(4)):434-437 doi:10.1002/hon.2670.

    PMID: 31465530

This page provides educational information about the genetic mutations associated with Essential Thrombocythemia (ET). It does not replace professional medical advice, diagnosis, or treatment from your hematologist.

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