The prevalence of JAK2, CALR, and MPL mutations in BCR-ABL1 rearrangement negative Iraqi patients
Main Article Content
Keywords
Myeloproliferative neoplasms; polycythemia vera; essential thrombocythemia; JAK2; CALR; MPL.
Abstract
Purpose: To date, there is no enough data about the prevalence of JAK2, CALR, and MPL mutations in BCR-ABL1 rearrangement negative myeloproliferative neoplasms (MPN) patients in Iraq. This study was conducted to determine the prevalence of these mutations and to evaluate the clinical features of polycythemia vera (PV) and essential thrombocythemia (ET) patients in Iraq.
Methods: we evaluated the presence of JAK2, CALR, and MPL mutations in 158 patients. JAK2V617F mutation was assessed using either Allele specific PCR or quantitative PCR. JAK2 negative MPN patients were further assessed for the existence of CALR, MPL, or JAK2 exon 12 mutations by quantitative PCR.
Results: JAK2V617F mutation was detected in 97.9% and 61.7% of PV and ET patients respectively, while JAK2 exon 12 was found in 2.1% of PV patients. CALR mutation was identified in 38.3% of ET patients. PV patients had higher level of hemoglobin, hematocrit, WBC, and neutrophil counts, and had lower levels of platelet count when compared to ET. CALR mutation was more prevalent in younger age groups, while JAK2V617F mutation predominantly found in older age groups. Greater number of PV patients (34.7%) developed splenomegaly at diagnosis than ET (12.7%). More thrombotic events were observed in PV than ET patients, but the result did not reach statistical significance.
Conclusion: The incidence of JAK2V617F, JAK2 exon 12, and CALR mutations in Iraqi MPN patients was similar to the previously published literature. In addition, we reconfirmed some clinical features of PV and ET patients described in literature.
References
1. Dickstein, JI and Vardiman, JW (1995) Hematopathologic findings in the myeloproliferative disorders. Semin Oncol 22(4): 355-373.
2. Dameshek, W (1951) Some speculations on the myeloproliferative syndromes. Blood 6(4): 372-375. https://doi.org/10.1182/blood.V6.4.372.372
3. Barbui, T, Thiele, J, Gisslinger, H, Kvasnicka, HM, Vannucchi, AM, Guglielmelli, P, Orazi, A and Tefferi, A (2018) The 2016 WHO
classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer Journal 8(2): 1-11. https://doi.org/10.1038/s41408-018-0054-y
4. Vainchenker, W and Kralovics, R (2017) Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood 129(6): 667-679. https://doi.org/10.1182/blood-2016-10-695940
5. Delhommeau, F, Jeziorowska, D, Marzac, C and Casadevall, N (2010) Molecular aspects of myeloproliferative neoplasms. International
Journal of Hematology 91(2): 165-173. https://doi.org/10.1007/s12185-010-0530-z
6. Scott, LM, Tong, W, Levine, RL, Scott, MA, Beer, PA, Stratton, MR, Futreal, PA, Erber, WN, McMullin, MF, Harrison, CN, Warren, AJ,
Gilliland, DG, Lodish, HF and Green, AR (2007) JAK2 Exon 12 Mutations in Polycythemia Vera and Idiopathic Erythrocytosis. New England Journal of Medicine 356(5): 459-468. https://doi.org/10.1056/NEJMoa065202
7. Guglielmelli, P, Pancrazzi, A, Bergamaschi, G, Rosti, V, Villani, L, Antonioli, E, Bosi, A, Barosi, G, Vannucchi, AM, Myelofibrosis, GIMEMA--Italian Registry of Myelofibrosis, and the MPD Research Consortium, C, IL, USA (2007) Anaemia characterises patients with myelofibrosis harbouring MplW515L/K mutation. British Journal of Haematology 137(3): 244-247. https://doi.org/10.1111/j.1365-2141.2007.06565.x
8. Nangalia, J, Massie, CE, Baxter, EJ, Nice, FL, Gundem, G, Wedge, DC, ... and Green, AR (2013) Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. New England Journal of Medicine 369(25): 2391-2405. https://doi.org/10.1056/NEJMoa1312542
9. Klampfl, T, Gisslinger, H, Harutyunyan, AS, Nivarthi, H, Rumi, E, Milosevic, JD, ... and Kralovics, R (2013) Somatic mutations of calreticulin in myeloproliferative neoplasms. New England Journal of Medicine 369(25): 2379-2390. https://doi.org/10.1056/NEJMoa1311347
10. Alvarez-Larrán, A, Ancochea, A, Angona, A, Pedro, C, García-Pallarols, F, Martínez-Avilés, L, ... and Besses, C (2012) Red cell mass
measurement in patients with clinically suspected diagnosis of polycythemia vera or essential thrombocythemia. Haematologica, 97(11), 1704-1707. https://doi.org/10.3324/haematol.2012.067348
11. Andriani, A, Latagliata, R, Anaclerico, B, Spadea, A, Rago, A, Di Veroli, A, ..... and Palandri, F (2016) Spleen enlargement is a risk factor for thrombosis in essential thrombocythemia: evaluation on 1,297 patients. American Journal of Hematology 91(3): 318-321. https://doi.org/10.1002/ajh.24269
12. Silver, RT, Taylor, E, III, Scandura, J and AbuZeinah, G (2021) Splenomegaly (SPML) in Polycythemia Vera (PV): Its Clinical Significance and Relation to Myelofibrosis and Survival. Blood 138(Supplement 1): 2580. https://doi.org/10.1182/blood-2021-149137
13. Jones, AV, Kreil, S, Zoi, K, Waghorn, K, Curtis, C, Zhang, L, ... and Cross, NC (2005) Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 106(6): 2162-2168. https://doi.org/10.1182/blood-2005-03-1320
14. Kralovics, R, Passamonti, F, Buser, AS, Teo, SS, Tiedt, R, Passweg, JR., Tichelli, A, Cazzola, M and Skoda, RC (2005) A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders. New England Journal of Medicine 352(17): 1779-1790. https://doi.org/10.1056/NEJMoa051113
15. Pardanani, AD, Levine, RL, Lasho, T, Pikman, Y, Mesa, RA, Wadleigh, M, .... and Tefferi, A (2006) MPL 515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 108(10): 3472-3476. https://doi.org/10.1182/blood-2006-04-018879
16. Singdong, R, Siriboonpiputtana, T, Chareonsirisuthigul, T, Kongruang, A, Limsuwanachot, N, Sirirat, T, Chuncharunee, S and Rerkamnuaychoke, B (2016) Characterization and Prognosis Significance of JAK2 (V617F), MPL, and CALR Mutations in Philadelphia-Negative Myeloproliferative Neoplasms. Asian Pacific Journal of Cancer Prevention 17(10): 4647-4653. https://doi.org/10.22034/APJCP.2016.17.10.4647
17. Baxter, EJ, Scott, LM, Campbell, PJ, East, C, Fourouclas, N, Swanton, S, Vassiliou, GS, Bench, AJ, Boyd, EM, Curtin, N, Scott, MA, Erber, WN and Green, AR (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. The Lancet, 365(9464): 1054-1061. https://doi.org/10.1016/S0140-6736(05)71142-9
18. Passamonti, F, Rumi, E, Pungolino, E, Malabarba, L, Bertazzoni, P, Valentini, M, Orlandi, E, Arcaini, L, Brusamolino, E, Pascutto,
C, Cazzola, M, Morra, E and Lazzarino, M (2004) Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. The American Journal of Medicine 117(10): 755-761. https://doi.org/10.1016/j.amjmed.2004.06.032
19. Lin, Y, Liu, E, Sun, Q, Ma, J, Li, Q, Cao, Z, Wang, J, Jia, Y, Zhang, H, Song, Z, Ai, X, Shi, L, Feng, X, Li, C, Wang, J and Ru, K (2015) The Prevalence of JAK2, MPL, and CALR Mutations in Chinese Patients With BCR-ABL1–Negative Myeloproliferative Neoplasms. American Journal of Clinical Pathology. 144(1):165-171. https://doi.org/10.1309/AJCPALP51XDIXDDV
20. Mejía-Ochoa, M, Acevedo Toro, PA, and Cardona-Arias, JA (2019) Systematization of analytical studies of polycythemia vera, essential thrombocythemia and primary myelofibrosis, and a meta-analysis of the frequency of JAK2, CALR and MPL mutations: 2000–2018. BMC
cancer 19(1): 1-15. https://doi.org/10.1186/s12885-019-5764-4
21. Daniela, P, Angela, B, Elisa, R, Sabrina, B, Chiara, E, Alessandro, P, Roberta, B, Maurizio, F, Francesco, P, Gianluca De, B, Laura, C and Mario, C (2011) Deep sequencing reveals double mutations in cis of MPL exon 10 in myeloproliferative neoplasms. Haematologica 96(4): 607-611. https://doi.org/10.3324/haematol.2010.034793
22. Palandri, F, Mora, B, Gangat, N and Catani, L (2021) Is there a gender effect in polycythemia vera?. Annals of Hematology 100(1): 11-25. https://doi.org/10.1007/s00277-020-04287-w
23. Iland, HJ, Laszlo, J, Case Jr, DC, Murphy, S, Reichert, TA., Tso, CY and Wasserman, LR (1987) Differentiation between essential thrombocythemia and polycythemia vera with marked thrombocytosis. American Journal of Hematology 25(2): 191-201.
https://doi.org/10.1002/ajh.2830250209
24. Pearson, TC and Wetherley-Mein, G (1978) Vascular occlusive episodes and venous hæmatocrit IN primary proliferative
polycythæmlx. The Lancet 312(8102): 1219-1222. https://doi.org/10.1016/S0140-6736(78)92098-6
25. Cerquozzi, S, Barraco, D, Lasho, T, Finke, C, Hanson, CA, Ketterling, RP, Pardanani, A, Gangat, N and Tefferi, A (2017) Risk factors for
arterial versus venous thrombosis in polycythemia vera: a single center experience in 587 patients. Blood Cancer Journal 7(12): 1-7. https://doi.org/10.1038/s41408-017-0035-6
26. Accurso, V, Santoro, M, Raso, S, Contrino, AD, Casimiro, P, Di Piazza, F, Perez, A, Russo, A and Siragusa, S (2019) Splenomegaly impacts prognosis in essential thrombocythemia and polycythemia vera: A single center study. Hematology Reports 11(4): 95-97. https://doi.org/10.4081/hr.2019.8281
27. Beer, PA, Campbell, PJ, Scott, LM., Bench, AJ, Erber, WN, Bareford, D, Wilkins, BS, Reilly, JT, Hasselbalch, HC, Bowman, R, Wheatley, K,
Buck, G, Harrison, CN and Green, AR (2008) MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 112(1): 141-149. https://doi.org/10.1182/blood-2008-01-131664
2. Dameshek, W (1951) Some speculations on the myeloproliferative syndromes. Blood 6(4): 372-375. https://doi.org/10.1182/blood.V6.4.372.372
3. Barbui, T, Thiele, J, Gisslinger, H, Kvasnicka, HM, Vannucchi, AM, Guglielmelli, P, Orazi, A and Tefferi, A (2018) The 2016 WHO
classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer Journal 8(2): 1-11. https://doi.org/10.1038/s41408-018-0054-y
4. Vainchenker, W and Kralovics, R (2017) Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood 129(6): 667-679. https://doi.org/10.1182/blood-2016-10-695940
5. Delhommeau, F, Jeziorowska, D, Marzac, C and Casadevall, N (2010) Molecular aspects of myeloproliferative neoplasms. International
Journal of Hematology 91(2): 165-173. https://doi.org/10.1007/s12185-010-0530-z
6. Scott, LM, Tong, W, Levine, RL, Scott, MA, Beer, PA, Stratton, MR, Futreal, PA, Erber, WN, McMullin, MF, Harrison, CN, Warren, AJ,
Gilliland, DG, Lodish, HF and Green, AR (2007) JAK2 Exon 12 Mutations in Polycythemia Vera and Idiopathic Erythrocytosis. New England Journal of Medicine 356(5): 459-468. https://doi.org/10.1056/NEJMoa065202
7. Guglielmelli, P, Pancrazzi, A, Bergamaschi, G, Rosti, V, Villani, L, Antonioli, E, Bosi, A, Barosi, G, Vannucchi, AM, Myelofibrosis, GIMEMA--Italian Registry of Myelofibrosis, and the MPD Research Consortium, C, IL, USA (2007) Anaemia characterises patients with myelofibrosis harbouring MplW515L/K mutation. British Journal of Haematology 137(3): 244-247. https://doi.org/10.1111/j.1365-2141.2007.06565.x
8. Nangalia, J, Massie, CE, Baxter, EJ, Nice, FL, Gundem, G, Wedge, DC, ... and Green, AR (2013) Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. New England Journal of Medicine 369(25): 2391-2405. https://doi.org/10.1056/NEJMoa1312542
9. Klampfl, T, Gisslinger, H, Harutyunyan, AS, Nivarthi, H, Rumi, E, Milosevic, JD, ... and Kralovics, R (2013) Somatic mutations of calreticulin in myeloproliferative neoplasms. New England Journal of Medicine 369(25): 2379-2390. https://doi.org/10.1056/NEJMoa1311347
10. Alvarez-Larrán, A, Ancochea, A, Angona, A, Pedro, C, García-Pallarols, F, Martínez-Avilés, L, ... and Besses, C (2012) Red cell mass
measurement in patients with clinically suspected diagnosis of polycythemia vera or essential thrombocythemia. Haematologica, 97(11), 1704-1707. https://doi.org/10.3324/haematol.2012.067348
11. Andriani, A, Latagliata, R, Anaclerico, B, Spadea, A, Rago, A, Di Veroli, A, ..... and Palandri, F (2016) Spleen enlargement is a risk factor for thrombosis in essential thrombocythemia: evaluation on 1,297 patients. American Journal of Hematology 91(3): 318-321. https://doi.org/10.1002/ajh.24269
12. Silver, RT, Taylor, E, III, Scandura, J and AbuZeinah, G (2021) Splenomegaly (SPML) in Polycythemia Vera (PV): Its Clinical Significance and Relation to Myelofibrosis and Survival. Blood 138(Supplement 1): 2580. https://doi.org/10.1182/blood-2021-149137
13. Jones, AV, Kreil, S, Zoi, K, Waghorn, K, Curtis, C, Zhang, L, ... and Cross, NC (2005) Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 106(6): 2162-2168. https://doi.org/10.1182/blood-2005-03-1320
14. Kralovics, R, Passamonti, F, Buser, AS, Teo, SS, Tiedt, R, Passweg, JR., Tichelli, A, Cazzola, M and Skoda, RC (2005) A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders. New England Journal of Medicine 352(17): 1779-1790. https://doi.org/10.1056/NEJMoa051113
15. Pardanani, AD, Levine, RL, Lasho, T, Pikman, Y, Mesa, RA, Wadleigh, M, .... and Tefferi, A (2006) MPL 515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 108(10): 3472-3476. https://doi.org/10.1182/blood-2006-04-018879
16. Singdong, R, Siriboonpiputtana, T, Chareonsirisuthigul, T, Kongruang, A, Limsuwanachot, N, Sirirat, T, Chuncharunee, S and Rerkamnuaychoke, B (2016) Characterization and Prognosis Significance of JAK2 (V617F), MPL, and CALR Mutations in Philadelphia-Negative Myeloproliferative Neoplasms. Asian Pacific Journal of Cancer Prevention 17(10): 4647-4653. https://doi.org/10.22034/APJCP.2016.17.10.4647
17. Baxter, EJ, Scott, LM, Campbell, PJ, East, C, Fourouclas, N, Swanton, S, Vassiliou, GS, Bench, AJ, Boyd, EM, Curtin, N, Scott, MA, Erber, WN and Green, AR (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. The Lancet, 365(9464): 1054-1061. https://doi.org/10.1016/S0140-6736(05)71142-9
18. Passamonti, F, Rumi, E, Pungolino, E, Malabarba, L, Bertazzoni, P, Valentini, M, Orlandi, E, Arcaini, L, Brusamolino, E, Pascutto,
C, Cazzola, M, Morra, E and Lazzarino, M (2004) Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. The American Journal of Medicine 117(10): 755-761. https://doi.org/10.1016/j.amjmed.2004.06.032
19. Lin, Y, Liu, E, Sun, Q, Ma, J, Li, Q, Cao, Z, Wang, J, Jia, Y, Zhang, H, Song, Z, Ai, X, Shi, L, Feng, X, Li, C, Wang, J and Ru, K (2015) The Prevalence of JAK2, MPL, and CALR Mutations in Chinese Patients With BCR-ABL1–Negative Myeloproliferative Neoplasms. American Journal of Clinical Pathology. 144(1):165-171. https://doi.org/10.1309/AJCPALP51XDIXDDV
20. Mejía-Ochoa, M, Acevedo Toro, PA, and Cardona-Arias, JA (2019) Systematization of analytical studies of polycythemia vera, essential thrombocythemia and primary myelofibrosis, and a meta-analysis of the frequency of JAK2, CALR and MPL mutations: 2000–2018. BMC
cancer 19(1): 1-15. https://doi.org/10.1186/s12885-019-5764-4
21. Daniela, P, Angela, B, Elisa, R, Sabrina, B, Chiara, E, Alessandro, P, Roberta, B, Maurizio, F, Francesco, P, Gianluca De, B, Laura, C and Mario, C (2011) Deep sequencing reveals double mutations in cis of MPL exon 10 in myeloproliferative neoplasms. Haematologica 96(4): 607-611. https://doi.org/10.3324/haematol.2010.034793
22. Palandri, F, Mora, B, Gangat, N and Catani, L (2021) Is there a gender effect in polycythemia vera?. Annals of Hematology 100(1): 11-25. https://doi.org/10.1007/s00277-020-04287-w
23. Iland, HJ, Laszlo, J, Case Jr, DC, Murphy, S, Reichert, TA., Tso, CY and Wasserman, LR (1987) Differentiation between essential thrombocythemia and polycythemia vera with marked thrombocytosis. American Journal of Hematology 25(2): 191-201.
https://doi.org/10.1002/ajh.2830250209
24. Pearson, TC and Wetherley-Mein, G (1978) Vascular occlusive episodes and venous hæmatocrit IN primary proliferative
polycythæmlx. The Lancet 312(8102): 1219-1222. https://doi.org/10.1016/S0140-6736(78)92098-6
25. Cerquozzi, S, Barraco, D, Lasho, T, Finke, C, Hanson, CA, Ketterling, RP, Pardanani, A, Gangat, N and Tefferi, A (2017) Risk factors for
arterial versus venous thrombosis in polycythemia vera: a single center experience in 587 patients. Blood Cancer Journal 7(12): 1-7. https://doi.org/10.1038/s41408-017-0035-6
26. Accurso, V, Santoro, M, Raso, S, Contrino, AD, Casimiro, P, Di Piazza, F, Perez, A, Russo, A and Siragusa, S (2019) Splenomegaly impacts prognosis in essential thrombocythemia and polycythemia vera: A single center study. Hematology Reports 11(4): 95-97. https://doi.org/10.4081/hr.2019.8281
27. Beer, PA, Campbell, PJ, Scott, LM., Bench, AJ, Erber, WN, Bareford, D, Wilkins, BS, Reilly, JT, Hasselbalch, HC, Bowman, R, Wheatley, K,
Buck, G, Harrison, CN and Green, AR (2008) MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 112(1): 141-149. https://doi.org/10.1182/blood-2008-01-131664
Article Sidebar
Published
Mar 13, 2023
Article Details
How to Cite
Aseel M. Al Dayyeni, Bassam T. Al-Gailani, Mohammed Ghanim Mahdi, & Mushtaq M. Khazeem. (2023). The prevalence of JAK2, CALR, and MPL mutations in BCR-ABL1 rearrangement negative Iraqi patients. Journal of Population Therapeutics and Clinical Pharmacology, 30(3), 443–451. https://doi.org/10.47750/jptcp.2023.30.03.046
Section
Articles
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
All articles published in JPTCP are licensed under Copyright Creative Commons Attribution-NonCommercial 4.0 International License.