Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Chronic Myeloproliferative Neoplasias

Loss of wild-type Jak2 allele enhances myeloid cell expansion and accelerates myelofibrosis in Jak2V617F knock-in mice

Leukemia volume 28, pages 1627–1635 (2014)Cite this article

Subjects

Abstract

JAK2V617F is the most common mutation found in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Although a majority of MPN patients carry heterozygous JAK2V617F mutation, loss of heterozygosity (LOH) on chromosome 9p (9pLOH) involving the JAK2 locus has been observed in ∼30% of MPN patients. JAK2V617F homozygosity via 9pLOH has been associated with more severe MPN phenotype. However, the contribution of 9pLOH in the pathogenesis of MPNs remains unclear. To investigate the roles of wild-type JAK2 (JAK2 WT) and JAK2V617F alleles in the development of MPNs, we have used conditional Jak2 knock-out and Jak2V617F knock-in mice and generated heterozygous, hemizygous and homozygous Jak2V617F mice. Whereas heterozygous Jak2V617F expression results in a polycythemia vera-like MPN in mice, loss of Jak2 WT allele in hemizygous or homozygous Jak2V617F mice results in markedly increased white blood cells, neutrophils, reticulocytes and platelets in the peripheral blood, and significantly larger spleen size compared with heterozygous Jak2V617F mice. Hemizygous or homozygous Jak2V617F mice also exhibit accelerated myelofibrosis compared with mice expressing heterozygous Jak2V617F. Together, these results suggest that loss of Jak2 WT allele increases the severity of the MPN. Thus, the Jak2 WT allele functions as a negative regulator of MPN induced by Jak2V617F.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C et al. A unique clonal JAK2 mutation leading to constitutive signaling causes polycythemia vera. Nature 2005; 434: 1144–1148.

    Article  CAS  PubMed  Google Scholar 

  2. 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: 387–397.

    Article  CAS  PubMed  Google Scholar 

  3. 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: 1054–1061.

    Article  CAS  PubMed  Google Scholar 

  4. 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 Eng J Med 2005; 352: 1779–1790.

    Article  CAS  Google Scholar 

  5. Zhao R, Xing S, Li Z, Fu X, Li Q, Krantz SB et al. Identification of an Acquired JAK2 Mutation in Polycythemia Vera. J Biol Chem 2005; 280: 22788–22792.

    Article  CAS  PubMed  Google Scholar 

  6. Kralovics R, Guan Y, Prchal JT . Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. Exp Hematol 2002; 30: 229–236.

    Article  CAS  PubMed  Google Scholar 

  7. Vannucchi AM, Antonioli E, Guglielmelli P, Longo G, Pancrazzi A, Ponziani V et al. Prospective identification of high-risk polycythemia vera patients based on JAK2(V617F) allele burden. Leukemia 2007; 21: 1952–1959.

    Article  CAS  PubMed  Google Scholar 

  8. Passamonti F, Rumi E, Pietra D, Elena C, Boveri E, Arcaini L et al. A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia 2010; 24: 1574–1579.

    Article  CAS  PubMed  Google Scholar 

  9. Silver RT, Vandris K, Wang YL, Adriano F, Jones AV, Christos PJ et al. JAK2(V617F) allele burden in polycythemia vera correlates with grade of myelofibrosis, but is not substantially affected by therapy. Leuk Res 2011; 35: 177–182.

    Article  CAS  PubMed  Google Scholar 

  10. 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: 3589–3597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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: 783–787.

    Article  CAS  PubMed  Google Scholar 

  12. 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: 584–596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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: 1528–1538.

    Article  CAS  PubMed  Google Scholar 

  14. Krempler A, Qi Y, Triplett AA, Zhu J, Rui H, Wagner KU . Generation of a conditional knockout allele for the Janus kinase 2 (Jak2) gene in mice. Genesis 2004; 40: 52–57.

    Article  CAS  PubMed  Google Scholar 

  15. Kühn R, Schwenk F, Aguet M, Rajewsky K . Inducible gene targeting in mice. Science 1995; 269: 1427–1429.

    Article  PubMed  Google Scholar 

  16. Mazharian A, Watson SP, Séverin S . Critical role for ERK1/2 in bone marrow and fetal liver-derived primary megakaryocyte differentiation, motility, and proplatelet formation. Exp Hematol 2009; 37: 1238–1249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. O'Keefe C, McDevitt MA, Maciejewski JP . Copy neutral loss of heterozygosity: a novel chromosomal lesion in myeloid malignancies. Blood 2010; 115: 2731–2739.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Whitman SP, Archer KJ, Feng L, Baldus C, Becknell B, Carlson BD et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res 2001; 61: 7233–7239.

    CAS  PubMed  Google Scholar 

  19. Raghavan M, Lillington DM, Skoulakis S, Debernardi S, Chaplin T, Foot NJ et al. Genome-wide single nucleotide polymorphism analysis reveals frequent partial uniparental disomy due to somatic recombination in acute myeloid leukemias. Cancer Res 2005; 65: 375–378.

    CAS  PubMed  Google Scholar 

  20. Szpurka H, Gondek LP, Mohan SR, Hsi ED, Theil KS, Maciejewski JP . UPD1p indicates the presence of MPL W515L mutation in RARS-T, a mechanism analogous to UPD9p and JAK2 V617F mutation. Leukemia 2008; 23: 610–614.

    Article  PubMed  Google Scholar 

  21. Wang X, Prakash S, Lu M, Tripodi J, Ye F, Najfeld V et al. Spleens of myelofibrosis patients contain malignant hematopoietic stem cells. J Clin Invest 2012; 122: 3888–3899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kubovcakova L, Lundberg P, Grisouard J, Hao-Shen H, Romanet V, Andraos R et al. Differential effects of hydroxyurea and INC424 on mutant allele burden and myeloproliferative phenotype in a JAK2-V617F polycythemia vera mouse model. Blood 2013; 121: 1188–1199.

    Article  CAS  PubMed  Google Scholar 

  23. Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell 1998; 93: 385–395.

    Article  CAS  PubMed  Google Scholar 

  24. Neubauer H, Cumano A, Müller M, Wu H, Huffstadt U, Pfeffer K . Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 1998; 93: 397–409.

    Article  CAS  PubMed  Google Scholar 

  25. Park SO, Wamsley HL, Bae K, Hu Z, Li X, Choe SW et al. Conditional deletion of Jak2 reveals an essential role in hematopoiesis throughout mouse ontogeny: implications for Jak2 inhibition in humans. PLoS One 2013; 8: e59675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li L, Bailey E, Greenblatt S, Huso D, Small D . Loss of the wild-type allele contributes to myeloid expansion and disease aggressiveness in FLT3/ITD knockin mice. Blood 2011; 118: 4935–4945.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dr Kay-Uwe Wagner (University of Nebraska, USA) for providing the Jak2-floxed mouse. This work was supported by the grants from the Leukemia and Lymphoma Society and US National Institute of Health (NIH; R01 HL095685) awarded to GM. GM is a Scholar of the Leukemia and Lymphoma Society.

Author Contributions

H Akada performed research, analyzed data and wrote the manuscript; S Akada performed research; RE Hutchison performed histopathologic analysis and revised the manuscript; G Mohi designed the research, analyzed data and wrote the manuscript.

Author information

Author notes

  1. H Akada and S Akada: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA

    H Akada, S Akada & G Mohi

  2. Department of Pathology, SUNY Upstate Medical University, Syracuse, NY, USA

    R E Hutchison

Authors
  1. H Akada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Akada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R E Hutchison
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G Mohi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G Mohi.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Akada, H., Akada, S., Hutchison, R. et al. Loss of wild-type Jak2 allele enhances myeloid cell expansion and accelerates myelofibrosis in Jak2V617F knock-in mice. Leukemia 28, 1627–1635 (2014). https://doi.org/10.1038/leu.2014.52

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2014.52

This article is cited by

Search

Advanced search

Quick links