Gender and age characteristics of JAK2 V617F mutation allelic burden and CALR and MPL driver mutations detection during primary examination of patients with suspected myeloproliferative neoplasms

Background. Detection of a somatic mutation in the Janus kinase 2 (JAK2) gene, along with mutations in the CALR and MPL genes, is one of the main criteria for diagnosing Ph-negative myeloproliferative neoplasms (MPN). At the same time, the JAK2 V617F mutation is often associated with agedependent clonal hematopoiesis of undetermined potential (CHIP). As a rule, the indicator reflecting the number of blood cells transformed by mutation – the mutant allelic burden (MAB) of JAK2 V617F in CHIP does not exceed 1–2 %, however, there is no clear boundary between the level of this indicator separating CHIP and MPN. The previously described “JAK2 paradox”, according to which JAK2 V617F positive CHIP predominates in men, and for women this mutation is more associated with MPN, suggests a different attitude to the diagnostic value of MAB between men and women. A separate issue concerns the detection of low MAB levels in combination with other MPN driver mutations.

Aim. To analyze the database of JAK2 V617F mutation allelic burden quantitative assessment results and to identify CALR and MPL genes driver mutations in patients depending on their age and gender.

Materials and methods. Data from records on the age and gender of 6210 patients (3061 men and 3149 women) were analyzed, in whom the JAK2 gene V617F somatic mutation in a quantitative format and MPL and CALR genes mutations were simultaneously determined. Of these, mutations were identified in 1226 women and 826 men with symptoms of MPN. Statistical analysis was performed using Excel spreadsheets and Statistica 10 package.

The results. The data obtained indicate that in women, compared to men, the frequency of the V617F mutation is higher in all age ranges. omen are also more likely to have mutations in the CALR and MPL genes. The gender and age dependence of identifying quantitative values of MAB JAK2 V617F differ significantly in the range of >1 and ˂ 1%. Also noteworthy is the fact of high detection (up to 17–27 %) of additional combined mutations in the CALR and MPL genes in patients with low MAB JAK2 V617F values.

Conclusion. The data support the gender “JAK2 paradox”, which suggests differential interpretation of test results in men and women. To more clearly assess the characteristics of the diagnostic value of MAN JAK2 V617F low levels and its dependence on the gender and age of patients, controlled multicenter clinical studies using standardized diagnostic test systems are needed.

1. Melikyan A.L., Kovrigina A.M., Subortseva I.N. et al. National Clinical Guidelines on diagnosis and treatment of Phnegative myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia, and primary myelofibrosis) (еdition 2020). Klinicheskaya onkogematologiya = Clinical Oncohematology 2021;14(2):262–98. (In Russ.).

2. Abdulkadyrov K.M., Shuvaev V.A., Martynkevich I.S. Myeloproliferative neoplasms. Moscow: Litterra, 2016. 298 p. (In Russ.).

3. PattersonFortin J., Moliterno A.R. Molecular pathogenesis of myeloproliferative neoplasms: influence of age and fender. Curr Hematol Malig Rep 2017;12(5):424–31. DOI: 10.1007/s1189901704110

4. Stuckey R., BilbaoSieyro C., SeguraDíaz A., GómezCasares M.T. Molecular studies for the early detection of philadelphianegative myeloproliferative neoplasms. Int J Mol Sci 2023;24(16):12700. DOI: 10.3390/ijms241612700

5. Cordua S., Kjaer L., Skov V. et al. Prevalence and phenotypes of JAK2 V617F and calreticulin mutations in a Danish general population. Blood 2019;134:469–79. DOI: 10.1182/blood.2019001113

6. Cordua S., Kjaer L., Skov V. et al. Early detection of myeloproliferative neoplasms in a Danish general population study. Leukemia 2021;35(9):2706–9. DOI: 10.1038/s41375021011598

7. Nielsen C., Bojesen S.E., Nordestgaard B.G. et al. JAK2V617F somatic mutation in the general population: myeloproliferative neoplasm development and progression rate. Haematologica 2014;99(9):1448–55. DOI: 10.3324/haematol.2014.107631

8. Hinds D.A., Barnholt K.E., Mesa R.A. et al. Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms. Blood 2016;128(8):1121–8. DOI: 10.1182/blood201506652941

9. Olkhovskiy I.A., Filina N.G., Gorbenko A.S. et al. Prevalence of mutations in JAK2 among blood donors. Gematologiya i transfuziologiya = Russian Journal of Hematology and Transfusiology 2018;63(1):65–70. (In Russ.). DOI: 10.25837/HAT.2018.49..1..006

10. Olkhovskiy I.A., Gorbenko A.S., Stolyar M.A. et al. Somatic mutation of the V617F JAK2 gene in patients of the cardiovascular diseases. Terapevticheskiy arkhiv = Therapeutic Archive 2019; 91(7):25–8. (In Russ.). DOI: 10.26442/00403660.2019.07.000245

11. Olkhovskiy I.A., Karapetyan G.E., Gorbenko A.S. et al. The identifiability of patients with carcinogenic somatic mutation of Junus kinase2 (V617FJAK2) within the framework of programs of dispensary and preventive examinations. Klinicheskaya laboratornaya diagnostika = Clinical Laboratory Diagnostics 2016;61(5):275–8. (In Russ.). DOI: 10.18821/086920842016615275278

12. Guo J., Walter K., Quiros P.M. et al. Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms. Nat Genet 2024;56(2):273–80. DOI: 10.1038/s4158802301638x

13. Warren J.T., Link D.C. Clonal hematopoiesis and risk for hematologic malignancy. Blood 2020;136(14):1599–605. DOI: 10.1182/blood.2019000991

14. Karantanos T., Kaizer H., Chaturvedi S. et al. Inflammation exerts a nonrandom risk in the acquisition and progression of the MPN: insights from a Mendelian randomization study. EClinicalMedicine 2020;21:100324. DOI: 10.1016/j.eclinm.2020.100324

15. Olkhovskiy I.А., Stolyar M.A., Komarovskiy Yu.Yu. et al. Study of the Janus kinase 2 (JAK2) gene haplotype 46/1 association with driver mutations of chronic Phnegative myeloproliferative neoplasms. Gematologiya i transfuziologiya = Russian Journal of Hematology and Transfusiology 2022;67(3):377–87. (In Russ.). DOI: 10.35754/023457302022673377387

16. Perner F., Perner C., Ernst T., Heidel F.H. Roles of JAK2 in aging, inflammation, hematopoiesis and malignant transformation. Cells 2019;8(8):854. DOI: 10.3390/cells8080854

17. Bick A.G., Weinstock J.S., Nandakumar S.K. et al. Inherited causes of clonal haematopoiesis in 97,691 whole genomes [published correction appears in Nature 2021;591(7851):E27]. Nature 2020;586(7831):763–8. DOI: 10.1038/s4158602028192

18. Robertson N.A., LatorreCrespo E., TerradasTerradas M. et al. Longitudinal dynamics of clonal hematopoiesis identifies gene specific fitness effects. Nat Med 2022;28(7):1439–46. DOI: 10.1038/s41591022018833

19. Korchagin V., Mironov K., Platonov A. et al. Application of the genetic risk model for the analysis of predisposition to nonlacunar ischemic stroke. Per Med 2019;16(5):369–78. DOI: 10.2217/pme20180104

20. AbuZeinah G., Di Giandomenico S., Choi D. et al. Hematopoietic fitness of JAK2 V617F myeloproliferative neoplasms is linked to clinical outcome. Blood Adv 2022;6(18):5477–81. DOI: 10.1182/bloodadvances.2022007128

21. Ahmed R.Z., Rashid M., Ahmed N. et al. Coexisting JAK2V617F and CALR Exon 9 mutations in myeloproliferative neoplasms – do they designate a new subtype? Asian Pac J Cancer Prev 2016;17(3):923–6. DOI: 10.7314/apjcp.2016.17.3

22. Langabeer S.E. Dual drivers in the myeloproliferative neoplasms: an underestimation? Technol Cancer Res Treat 2023;22:15330338231179561. DOI: 10.1177/15330338231179561

23. Gorbenko A.S., Stolyar M.A., Olkhovskiy I.A. et al. Parallel algorithm for myeloproliferative neoplasms testing: the frequency of double mutations is found in the JAK2/MPL genes more often than the JAK2/CALR genes, but is there a clinical benefit? Clin Chem Lab Med 2019;57(4):e60–2. DOI: 10.1515/cclm20180232

24. Subbotina T.N., Olkhovskiy I., Shaikhutdinova R. et al. What is the secret of the JAK2 mutation allele load stability in some patients with MPN? Haematologica 2016;101(S1):814–5.

25. Wu S., Luo P., Rouzi T. et al. The combination of JAK2V617F allele burden and WT1 expression can be helpful in distinguishing the subtype of MPN Patients. Cancer Control 2023;30:10732748231163648. DOI: 10.1177/10732748231163648