Skip to main content
SpringerLink
Log in

The role of driver mutations in myeloproliferative neoplasms: insights from mouse models

  • Progress in Hematology
  • Progress in elucidation of molecular pathophysiology and its application to therapeutic decisions of MPNs
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

High frequency of JAK2V617F or CALR exon 9 mutations is a main molecular feature of myeloproliferative neoplasms (MPNs). Analysis of mouse models driven by these mutations suggests that they are a direct cause of MPNs and that the expression levels of the mutated genes define the disease phenotype. The function of MPN-initiating cells has also been elucidated by these mouse models. Such mouse models also play an important role in modeling disease to investigate the effects and action mechanisms of therapeutic drugs, such as JAK2 inhibitors and interferon α, against MPNs. The mutation landscape of hematological tumors has already been clarified by next-generation sequencing technology, and the importance of functional analysis of mutant genes in vivo should increase further in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7(4):387–97.

    CAS  PubMed  Google Scholar 

  2. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):1779–90.

    CAS  PubMed  Google Scholar 

  3. James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144–8.

    CAS  PubMed  Google Scholar 

  4. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):1054–61.

    CAS  PubMed  Google Scholar 

  5. Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017;129(6):667–79.

    CAS  PubMed  Google Scholar 

  6. Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391–405.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379–90.

    CAS  PubMed  Google Scholar 

  8. Jiang Y, Dey S, Matsunami H. Calreticulin: roles in cell-surface protein expression. Membranes. 2014;4(3):630–41.

    PubMed  PubMed Central  Google Scholar 

  9. Shide K, Kameda T, Yamaji T, Sekine M, Inada N, Kamiunten A, et al. Calreticulin mutant mice develop essential thrombocythemia that is ameliorated by the JAK inhibitor ruxolitinib. Leukemia. 2017;31(5):1136–44.

    CAS  PubMed  Google Scholar 

  10. Chachoua I, Pecquet C, El-Khoury M, Nivarthi H, Albu R-I, Marty C, et al. Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants. Blood. 2016;127:1325–35.

    CAS  PubMed  Google Scholar 

  11. Araki M, Yang Y, Masubuchi N, Hironaka Y, Takei H, Morishita S, et al. Activation of the thrombopoietin receptor by mutant calreticulin in CALR-mutant myeloproliferative neoplasms. Blood. 2016;127(10):1307–16.

    CAS  PubMed  Google Scholar 

  12. Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3(7):e270.

    PubMed  PubMed Central  Google Scholar 

  13. Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M, et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood. 2006;108(10):3472–6.

    CAS  PubMed  Google Scholar 

  14. Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356(5):459–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Yao H, Ma Y, Hong Z, Zhao L, Monaghan SA, Hu MC, et al. Activating JAK2 mutants reveal cytokine receptor coupling differences that impact outcomes in myeloproliferative neoplasm. Leukemia. 2017;31:2122.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Pietra D, Li S, Brisci A, Passamonti F, Rumi E, Theocharides A, et al. Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders. Blood. 2008;111:1686–9.

    CAS  PubMed  Google Scholar 

  17. Bumm TG, Elsea C, Corbin AS, Loriaux M, Sherbenou D, Wood L, et al. Characterization of murine JAK2V617F-positive myeloproliferative disease. Cancer Res. 2006;66(23):11156–65.

    CAS  PubMed  Google Scholar 

  18. Lacout C, Pisani DF, Tulliez M, Gachelin FM, Vainchenker W, Villeval JL. JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis. Blood. 2006;108(5):1652–60.

    CAS  PubMed  Google Scholar 

  19. Wernig G, Mercher T, Okabe R, Levine RL, Lee BH, Gilliland DG. Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood. 2006;107(11):4274–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Zaleskas VM, Krause DS, Lazarides K, Patel N, Hu Y, Li S, et al. Molecular pathogenesis and therapy of polycythemia induced in mice by JAK2 V617F. PLoS ONE. 2006;1:e18.

    PubMed  PubMed Central  Google Scholar 

  21. Tiedt R, Hao-Shen H, Sobas MA, Looser R, Dirnhofer S, Schwaller J, et al. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood. 2008;111(8):3931–40.

    CAS  PubMed  Google Scholar 

  22. Shide K, Shimoda HK, Kumano T, Karube K, Kameda T, Takenaka K, et al. Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F. Leukemia. 2008;22(1):87–95.

    CAS  PubMed  Google Scholar 

  23. Domen J, Gandy KL, Weissman IL. Systemic overexpression of BCL-2 in the hematopoietic system protects transgenic mice from the consequences of lethal irradiation. Blood. 1998;91(7):2272–82.

    CAS  PubMed  Google Scholar 

  24. Barbui T, Barosi G, Grossi A, Gugliotta L, Liberato LN, Marchetti M, et al. Practice guidelines for the therapy of essential thrombocythemia. A statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica. 2004;89(2):215–32.

    CAS  PubMed  Google Scholar 

  25. De Stefano V, Za T, Rossi E, Vannucchi AM, Ruggeri M, Elli E, et al. Increased risk of recurrent thrombosis in patients with essential thrombocythemia carrying the homozygous JAK2 V617F mutation. Ann Hematol. 2010;89(2):141–6.

    PubMed  Google Scholar 

  26. Scott LM, Scott MA, Campbell PJ, Green AR. Progenitors homozygous for the V617F mutation occur in most patients with polycythemia vera, but not essential thrombocythemia. Blood. 2006;108(7):2435–7.

    CAS  PubMed  Google Scholar 

  27. Li J, Spensberger D, Ahn JS, Anand S, Beer PA, Ghevaert C, et al. JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia. Blood. 2010;116(9):1528–38.

    CAS  PubMed  Google Scholar 

  28. Akada H, Yan D, Zou H, Fiering S, Hutchison RE, Mohi MG. Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease. Blood. 2010;115(17):3589–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Marty C, Lacout C, Martin A, Hasan S, Jacquot S, Birling MC, et al. Myeloproliferative neoplasm induced by constitutive expression of JAK2V617F in knock-in mice. Blood. 2010;116(5):783–7.

    CAS  PubMed  Google Scholar 

  30. Mullally A, Lane SW, Ball B, Megerdichian C, Okabe R, Al-Shahrour F, et al. Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells. Cancer Cell. 2010;17(6):584–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Li J, Kent DG, Godfrey AL, Manning H, Nangalia J, Aziz A, et al. JAK2V617F homozygosity drives a phenotypic switch in myeloproliferative neoplasms, but is insufficient to sustain disease. Blood. 2014;123:3139–51.

    CAS  PubMed  Google Scholar 

  32. Skoda RC. JAK2 impairs stem cell function? Blood. 2010;116(9):1392–3.

    CAS  PubMed  Google Scholar 

  33. Li J, Kent DG, Chen E, Green AR. Mouse models of myeloproliferative neoplasms: JAK of all grades. Dis Model Mech. 2011;4(3):311–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Van Etten RA, Koschmieder S, Delhommeau F, Perrotti D, Holyoake T, Pardanani A, et al. The Ph-positive and Ph-negative myeloproliferative neoplasms: some topical pre-clinical and clinical issues. Haematologica. 2011;96(4):590–601.

    PubMed  PubMed Central  Google Scholar 

  35. Mullally A, Poveromo L, Schneider RK, Al-Shahrour F, Lane SW, Ebert BL. Distinct roles for long-term hematopoietic stem cells and erythroid precursor cells in a murine model of Jak2V617F-mediated polycythemia vera. Blood. 2012;120(1):166–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Hasan S, Lacout C, Marty C, Cuingnet M, Solary E, Vainchenker W, et al. JAK2V617F expression in mice amplifies early hematopoietic cells and gives them a competitive advantage that is hampered by IFNα. Blood. 2013;122(8):1464–77.

    CAS  PubMed  Google Scholar 

  37. Kent DG, Li J, Tanna H, Fink J, Kirschner K, Pask DC, et al. Self-renewal of single mouse hematopoietic stem cells is reduced by JAK2V617F without compromising progenitor cell expansion. PLoS Biol. 2013;11(6):e1001576.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Grinfeld J, Godfrey AL. After 10 years of JAK2V617F: disease biology and current management strategies in polycythaemia vera. Blood Rev. 2017;31(3):101–18.

    CAS  PubMed  Google Scholar 

  39. Nangalia J, Green AR. Myeloproliferative neoplasms: from origins to outcomes. Blood. 2017;130(23):2475–83.

    CAS  PubMed  Google Scholar 

  40. Nangalia J, Nice FL, Wedge DC, Godfrey AL, Grinfeld J, Thakker C, et al. DNMT3A mutations occur early or late in patients with myeloproliferative neoplasms and mutation order influences phenotype. Haematologica. 2015;100:e438–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Ortmann CA, Kent DG, Nangalia J, Silber Y, Wedge DC, Grinfeld J, et al. Effect of mutation order on myeloproliferative neoplasms. N Engl J Med. 2015;372(7):601–12.

    PubMed  PubMed Central  Google Scholar 

  42. Elf S, Abdelfattah NS, Chen E, Perales-Patón J, Rosen EA, Ko A, et al. Mutant calreticulin requires both its mutant C-terminus and the thrombopoietin receptor for oncogenic transformation. Cancer Discov. 2016;6:368–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Marty C, Pecquet C, Nivarthi H, El-Khoury M, Chachoua I, Tulliez M, et al. Calreticulin mutants in mice induce an MPL-dependent thrombocytosis with frequent progression to myelofibrosis. Blood. 2016;127:1317–24.

    CAS  PubMed  Google Scholar 

  44. Shide K, Kameda T, Kamiunten A, Sekine M, Ozono Y, Yokomizo T, et al. Haploinsufficiency of CALR confers hematopoietic stem cells (HSCs) with a clonal advantage over wild-type cells, and, in setting of myeloproliferative neoplasms, compensates for the functions of HSCs impaired by the CALR mutation. Blood. 2018;132(1):97.

    Google Scholar 

  45. Shide K, Kameda T, Kamiunten A, Oji A, Ozono Y, Sekine M, et al. Mice with Calr mutations homologous to human CALR mutations only exhibit mild thrombocytosis. Blood Cancer J. 2019;9(4):42.

    PubMed  PubMed Central  Google Scholar 

  46. Balligand T, Achouri Y, Pecquet C, Gaudray G, Colau D, Hug E, et al. Knock-in of murine Calr del52 induces essential thrombocythemia with slow-rising dominance in mice and reveals key role of Calr exon 9 in cardiac development. Leukemia. 2019;. https://doi.org/10.1038/s41375-019-0538-1.

    Article  PubMed  Google Scholar 

  47. Balligand T, Achouri Y, Chachoua I, Pecquet C, Defour J-P, Constantinescu SN. Crispr/Cas9 engineered 61 bp deletion in the Calr gene of mice leads to development of thrombocytosis. Blood. 2016;128:4274.

    Google Scholar 

  48. Li J, Prins D, Park HJ, Grinfeld J, Gonzalez-Arias C, Loughran S, et al. Mutant calreticulin knockin mice develop thrombocytosis and myelofibrosis without a stem cell self-renewal advantage. Blood. 2018;131(6):649–61.

    CAS  PubMed  Google Scholar 

  49. Kameda T, Shide K, Yamaji T, Kamiunten A, Sekine M, Taniguchi Y, et al. Loss of TET2 has dual roles in murine myeloproliferative neoplasms: disease sustainer and disease accelerator. Blood. 2015;125:304–15.

    CAS  PubMed  Google Scholar 

  50. Chen E, Schneider RK, Breyfogle LJ, Rosen EA, Poveromo L, Elf S, et al. Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice promote disease progression in myeloproliferative neoplasms. Blood. 2015;125(2):327–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Sashida G, Wang C, Tomioka T, Oshima M, Aoyama K, Kanai A, et al. The loss of Ezh2 drives the pathogenesis of myelofibrosis and sensitizes tumor-initiating cells to bromodomain inhibition. J Exp Med. 2016;213(8):1459–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Shimizu T, Kubovcakova L, Nienhold R, Zmajkovic J, Meyer SC, Hao-Shen H, et al. Loss of Ezh2 synergizes with JAK2-V617F in initiating myeloproliferative neoplasms and promoting myelofibrosis. J Exp Med. 2016;213:1479–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Yang Y, Akada H, Nath D, Hutchison RE, Mohi G. Loss of Ezh2 cooperates with Jak2V617F in the development of myelofibrosis in a mouse model of myeloproliferative neoplasm. Blood. 2016;127(26):3410–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Guo Y, Zhou Y, Yamatomo S, Yang H, Zhang P, Chen S, et al. ASXL1 alteration cooperates with JAK2V617F to accelerate myelofibrosis. Leukemia. 2019;33(5):1287–91.

    PubMed  Google Scholar 

  55. Jacquelin S, Straube J, Cooper L, Vu T, Song A, Bywater M, et al. Jak2V617F and Dnmt3a loss cooperate to induce myelofibrosis through activated enhancer-driven inflammation. Blood. 2018;132(26):2707.

    CAS  PubMed  Google Scholar 

  56. McKenney AS, Lau AN, Somasundara AVH, Spitzer B, Intlekofer AM, Ahn J, et al. JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition. J Clin Investig. 2018;128(2):789–804.

    PubMed  PubMed Central  Google Scholar 

  57. Tyner JW, Bumm TG, Deininger J, Wood L, Aichberger KJ, Loriaux MM, et al. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood. 2010;115(25):5232–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Wernig G, Kharas MG, Okabe R, Moore SA, Leeman DS, Cullen DE, et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell. 2008;13(4):311–20.

    CAS  PubMed  Google Scholar 

  59. Nakaya Y, Shide K, Niwa T, Homan J, Sugahara S, Horio T, et al. Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms. Blood Cancer J. 2011;1(7):e29.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Shide K, Kameda T, Markovtsov V, Shimoda HK, Tonkin E, Fang S, et al. R723, a selective JAK2 inhibitor, effectively treats JAK2V617F-induced murine myeloproliferative neoplasm. Blood. 2011;117(25):6866–75.

    CAS  PubMed  Google Scholar 

  61. Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–98.

    CAS  PubMed  Google Scholar 

  62. Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. 2011;29(7):789–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Quintas-Cardama A, Kantarjian H, Manshouri T, Luthra R, Estrov Z, Pierce S, et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol. 2009;27(32):5418–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Kiladjian JJ, Cassinat B, Chevret S, Turlure P, Cambier N, Roussel M, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065–72.

    CAS  PubMed  Google Scholar 

  66. Mullally A, Bruedigam C, Poveromo L, Heidel FH, Purdon A, Vu T, et al. Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-alpha in a murine model of polycythemia vera. Blood. 2013;121(18):3692–702.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Essers MA, Offner S, Blanco-Bose WE, Waibler Z, Kalinke U, Duchosal MA, et al. IFNalpha activates dormant haematopoietic stem cells in vivo. Nature. 2009;458(7240):904–8.

    CAS  PubMed  Google Scholar 

  68. Sato T, Onai N, Yoshihara H, Arai F, Suda T, Ohteki T. Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon-dependent exhaustion. Nat Med. 2009;15(6):696–700.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan

    Kotaro Shide

Authors
  1. Kotaro Shide
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kotaro Shide.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shide, K. The role of driver mutations in myeloproliferative neoplasms: insights from mouse models. Int J Hematol 111, 206–216 (2020). https://doi.org/10.1007/s12185-019-02803-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-019-02803-x

Keywords

Search

Navigation