JAK2V617F mediates resistance to DNA damage-induced apoptosis by modulating FOXO3A localization and Bcl-xL deamidation

Ahn, J.S., Li, J., Chen, E., Kent, D.G., Park, H.J. and Green, A.R. 2016. JAK2V617F mediates resistance to DNA damage-induced apoptosis by modulating FOXO3A localization and Bcl-xL deamidation. Oncogene. 35, pp. 2235-2246. https://doi.org/10.1038/onc.2015.285

TitleJAK2V617F mediates resistance to DNA damage-induced apoptosis by modulating FOXO3A localization and Bcl-xL deamidation
TypeJournal article
AuthorsAhn, J.S., Li, J., Chen, E., Kent, D.G., Park, H.J. and Green, A.R.
Abstract

The JAK2V617F mutation is found in most patients with a myeloproliferative neoplasm (MPN). This gain-of-function mutation dysregulates cytokine signaling and is associated with increased accumulation of DNA damage, a process likely to drive disease evolution. JAK2V617F inhibits NHE-1 upregulation in response to DNA damage and consequently represses Bcl-xL deamidation and apoptosis, thus giving rise to inappropriate cell survival. However, the mechanism whereby NHE-1 expression is inhibited by JAK2V617F is unknown. In this study, we demonstrate that the accumulation of reactive oxygen species (ROS) in cells expressing JAK2V617F compromises the NHE-1/Bcl-xL deamidation pathway by repressing NHE-1 upregulation in response to DNA damage. In JAK2V617F-positive cells, increased ROS levels results from aberrant PI3K signaling, which decreases nuclear localization of FOXO3A and decreases catalase expression. Furthermore, when compared with autologous control erythroblasts, clonally derived JAK2V617F-positive erythroblasts from MPN patients displayed increased ROS levels and reduced nuclear FOXO3A. However, in hematopoietic stem cells (HSCs), FOXO3A is largely localized within the nuclei despite the presence of JAK2V617F mutation, suggesting that JAK2-FOXO signaling has a different effect on progenitors compared with stem cells. Inactivation of FOXO proteins and elevation of intracellular ROS are characteristics common to many cancers, and hence these findings are likely to be of relevance beyond the MPN field.

JournalOncogene
Journal citation35, pp. 2235-2246
ISSN0950-9232
Year2016
PublisherNature Publishing Group
Digital Object Identifier (DOI)https://doi.org/10.1038/onc.2015.285

Related outputs

Zinc-dependent multimerization of mutant calreticulin is required for MPL binding and MPN pathogenesis
Rivera, J.F., Baral, A.J., Nadat, F., Boyd, G., Smyth, R., Patel, H., Burman, E.L., Alameer, G., Boxall, S.A., Jackson, B.R., Baxter, E.J., Laslo, P., Green, A.R., Kent, D.G., Mullally, A. and Chen, E. 2021. Zinc-dependent multimerization of mutant calreticulin is required for MPL binding and MPN pathogenesis. Blood Advances. 5 (7), pp. 1922-1932. https://doi.org/10.1182/bloodadvances.2020002402

Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML
Tothova, Z., Valton, A., Gorelov, R., Vallurupalli, M., Krill-Burger, J.M., Holmes, A., Landers, C.C., Haydu, J.E., Malolepsza, E., Hartigan, C.R., Donahue, M., Popova, K.D., Koochaki, S.H.J., Venev, S.V., Rivera, J.F., Chen, E., Lage, K., Schenone, M., D'Andrea, A.D., Carr, S.A., Morgan, E.A., Dekker, J. and Ebert, B.L. 2021. Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML. JCI Insight. 6 (3) e142149. https://doi.org/10.1172/jci.insight.142149

Mechanism of completion of peptidyltransferase centre assembly in eukaryotes
Kargas, V., Castro-Hartmann, P., Escudero-Urquijo, N., Dent, K., Hilcenko, C., Sailer, C., Zisser, G., Marques-Carvalho, M.J., Pellegrino, S., Wawiorka, L., Freund, S.M., Wagstaff, J.L., Andreeva, A., Faille, A., Chen, E., Stengel, F., Bergler, H. and Warren, A.J. 2019. Mechanism of completion of peptidyltransferase centre assembly in eukaryotes. eLife. 8, p. e44904 e44904. https://doi.org/10.7554/eLife.44904

Defining the requirements for the pathogenic interaction between mutant calreticulin and MPL in MPN
Elf, S., Abdelfattah, N.S., Baral, A.J., Beeson, D., Rivera, J.F., Ko, A., Florescu, N., Birrane, G., Chen, E. and Mullally, A. 2018. Defining the requirements for the pathogenic interaction between mutant calreticulin and MPL in MPN. Blood. 131 (7), pp. 782-786. https://doi.org/10.1182/blood-2017-08-800896

STAT1 activation in association with JAK2 exon 12 mutations
Godfrey, A.L., Chen, E., Massie, C.E., Silber, Y., Pagano, F., Bellosillo, B., Guglielmelli, P., Harrison, C.N., Reilly, J.T., Stegelmann, F., Bijou, F., Lippert, E., Boiron, J.M., Dohner, K., Vannucchi, A.M., Besses, C. and Green, A.R. 2016. STAT1 activation in association with JAK2 exon 12 mutations. Haematologica. 101, pp. e15-e19. https://doi.org/10.3324/haematol.2015.128546

Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9
Schneider, R.K., Schenone, M., Ferreira, M.V., Kramann, R., Joyce, C.E., Hartigan, C., Beier, F., Brümmendorf, T.H., Germing, U., Platzbecker, U., Busche, G., Knuchel, R., Chen, M.C., Waters, C.S., Chen, E., Chu, L.P., Novina, C.D., Lindsley, R.C., Carr, S.A. and Ebert, B.L. 2016. Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9. Nature Medicine. 22, pp. 288-297. https://doi.org/10.1038/nm.4047

Mutant Calreticulin Requires Both Its Mutant C-terminus and the Thrombopoietin Receptor for Oncogenic Transformation
Elf, S., Abdelfattah, N.S., Chen, E., Perales-Patón, J., Rosen, E.A., Ko, A., Peskier, F., Florescu, N., Giannini, S., Wolach, O., Morgan, E.A., Tothova, Z., Losman, J.A., Schneider, R.K., Al-Shahrour, F. and Mullally, A. 2016. Mutant Calreticulin Requires Both Its Mutant C-terminus and the Thrombopoietin Receptor for Oncogenic Transformation. Cancer Discovery. 6, pp. 368-381. https://doi.org/10.1158/2159-8290.CD-15-1434

Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice combine to promote disease progression in myeloproliferative neoplasms
Chen, E., Schneider, R.K., Breyfogle, L.J., Rosen, E.A., Poveromo, L., Elf, S., Ko, A., Brumme, K., Levine, R., Ebert, B.L. and Mullally, A. 2015. Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice combine to promote disease progression in myeloproliferative neoplasms. Blood. 125, pp. 327-335. https://doi.org/10.1182/blood-2014-04-567024

Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms
Tapper, W., Jones, A.V., Kralovics, R., Harutyunyan, A.S., Zoi, K., Leung, W., Godfrey, A.L., Guglielmelli, P., Callaway, A., Ward, D., Aranaz, P., White, H.E., Waghorn, K., Lin, F., Chase, A., Baxter, E.J., Maclean, C., Nangalia, J., Chen, E., Evans, P., Short, M., Jack, A., Wallis, L., Oscier, D., Duncombe, A.S., Schuh, A., Mead, A.J., Griffiths, M., Ewing, J., Gale, R.E., Schnittger, S., Haferlach, T., Stegelmann, F., Dohner, K., Grallert, H., Strauch, K., Tanaka, T., Bandinelli, S., Giannopoulos, A., Pieri, L., Mannarelli, C., Gisslinger, H., Barosi, G., Cazzola, M., Reiter, A., Harrison, C., Campbell P., Green, A.R., Vannucchi, A. and Cross N.C. 2015. Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms. Nature Communications . 6 6691. https://doi.org/10.1038/ncomms7691

RECQL5 suppresses oncogenic JAK2-induced replication stress and genomic instability
Chen, E., Ahn, J.S., Sykes, D.B., Breyfogle, L.J., Godfrey, A.L., Nangalia, J., Ko, A., DeAngelo, D.J., Green, A.R. and Mullally, A. 2015. RECQL5 suppresses oncogenic JAK2-induced replication stress and genomic instability. Cell Reports. 13, pp. 2345-2532. https://doi.org/10.1016/j.celrep.2015.11.037

JAK2V617F homozygosity drives a phenotypic switch in myeloproliferative neoplasms, but is insufficient to sustain disease
Li, J., Kent, D.G., Godfrey, A.L., Manning, H., Nangalia, J., Aziz, A., Chen, E., Saeb-Parsy, K., Find, J., Sneade, R., Hamilton, T.L., Pask, D.C., Silber, Y., Zhao, X., Ghevaert, C., Liu, P. and Green, A.R. 2014. JAK2V617F homozygosity drives a phenotypic switch in myeloproliferative neoplasms, but is insufficient to sustain disease. Blood. 123, pp. 3139-3151. https://doi.org/10.1182/blood-2013-06-510222

JAK2V617F promotes replication fork stalling with disease-restricted impairment of the intra-S checkpoint response
Chen, E., Ahn, J.S., Massie, C.E., Clynes, D., Godfrey, A.L., Li, J., Park, H.J., Nangalia, J., Silber, Y., Mullally, A., Gibbons, R.J. and Green, A.R. 2014. JAK2V617F promotes replication fork stalling with disease-restricted impairment of the intra-S checkpoint response. Proceedings of the National Academy of Sciences of the United States of America. 111, pp. 15190-15195. https://doi.org/10.1073/pnas.1401873111

How does JAK2V617F contribute to pathogenesis of myeloproliferative neoplasms? (Review)
Chen, E. and Mullally, A. 2014. How does JAK2V617F contribute to pathogenesis of myeloproliferative neoplasms? (Review). Hematology American Society of Hematology Education Program. 2014, pp. 268-276. https://doi.org/10.1182/asheducation-2014.1.268

Clonal analysis reveal associations of JAK2V617F homozygosity with hematological features, age and gender in PV and ET
Godfrey, A.L., Chen, E., Pagano, F., Silber, Y., Campbell, P.J. and Green, A.R. 2013. Clonal analysis reveal associations of JAK2V617F homozygosity with hematological features, age and gender in PV and ET. Haematologica. 98, pp. 718-721. https://doi.org/10.3324/haematol.2012.079129

JAK2V617F homozygosity arises commonly and recurrently in PV and ET, but PV is characterized by expansion of a dominant homozygous subclone
Godfrey, A.L., Chen, E., Pagano, F., Ortmann, C.A., Silber, Y., Belosillo, B., Guglielmelli, P., Harrison, C., Reilly, J.T., Stegelmann, F., Bijou, F., Lippert, E., McMullin, M.F., Boiron, J.M., Doehner, K., Vannucchi, A.M., Besses, C., Campbell, P.J. and Green, A.R. 2012. JAK2V617F homozygosity arises commonly and recurrently in PV and ET, but PV is characterized by expansion of a dominant homozygous subclone. Blood. 120, pp. 2704-2707. https://doi.org/10.1182/blood-2012-05-431791

Janus kinase deregulation in leukemia and lymphoma (Review)
Chen, E., Staudt, L.M. and Green, A.R. 2012. Janus kinase deregulation in leukemia and lymphoma (Review). Immunity. 36 (4), pp. 529-541. https://doi.org/10.1016/j.immuni.2012.03.017

Mouse models of myeloproliferative Neoplasms: JAK of all grades. (Review)
Li, J., Kent, D.G., Chen, E. and Green, A.R. 2011. Mouse models of myeloproliferative Neoplasms: JAK of all grades. (Review). Disease Models and Mechanisms. 4, pp. 311-317. https://doi.org/10.1242/dmm.006817

Two routes to leukemic transformation following a JAK2 mutation-positive myeloproliferative neoplasm
Beer, P.A., Delhommeau, F., Lecouedic, J.P., Dawson, M.A., Chen, E., Bareford, D., Kusec, R., McMullin, M.F., Harrison, C.N., Vannucchi, A., Vainchenker, W. and Green, A.R. 2010. Two routes to leukemic transformation following a JAK2 mutation-positive myeloproliferative neoplasm. Blood. 115, pp. 2891-2900. https://doi.org/10.1182/blood-2009-08-236596

JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia
Li, J., Spensberger, D., Ahn, J.S., Anand, S., Beer, P.A., Ghevaert, C., Chen, E., Forrai, A., Scott, L.M., Ferreira, R., Campbell, P.J., Watson, S.P., Liu, P., Erber, W.N., Huntly, B.J., Ottersbach, K. and Green, A.R. 2010. JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia. Blood. 116, pp. 1528-1538. https://doi.org/10.1182/blood-2009-12-259747

Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling
Chen, E., Beer, P.A., Godfrey, A.L., Ortmann, C.A., Li, J., Costa-Pereira, A.P., Ingle, C.E., Dermitzakis, E.T., Campbell, P.J. and Green, A.R. 2010. Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling. Cancer Cell. 18, pp. 524-535. https://doi.org/10.1016/j.ccr.2010.10.013

Id1 promotes expansion and survival of primary erythroid cells and is a target of JAK2V617F-STAT5 signalling
Wood, A.D., Chen, E., Donaldson, I.J., Hattangadi, S., Burke, K.A., Dawson, M.A., Miranda-Saavendra, D., Lodish, H.F., Green, A.R. and Gottgens, B. 2009. Id1 promotes expansion and survival of primary erythroid cells and is a target of JAK2V617F-STAT5 signalling. Blood. 114, pp. 1820-1830. https://doi.org/10.1182/blood-2009-02-206573

Dysregulated expression of mitotic regulators is associated with B-cell lymphomagenesis in HOX11-Transgenic mice
Chen, E., Lim, M.S., Rosic-Kablar, S., Liu, J., Jolicoeur, P., Dube, I.D. and Hough, M.R. 2006. Dysregulated expression of mitotic regulators is associated with B-cell lymphomagenesis in HOX11-Transgenic mice. Oncogene. 25, pp. 2575-2587. https://doi.org/10.1038/sj.onc.1209285

Loss of UBR1 promotes aneuploidy and accelerates B cell lymphomagenesis in TLX1/HOX11-Transgenic mice
Chen, E., Kwon, Y.T., Lim, M.S., Dube, I.D. and Hough, M.R. 2006. Loss of UBR1 promotes aneuploidy and accelerates B cell lymphomagenesis in TLX1/HOX11-Transgenic mice. Oncogene. 25, pp. 5752-5763. https://doi.org/10.1038/sj.onc.1209573

Permalink - https://westminsterresearch.westminster.ac.uk/item/qy561/jak2v617f-mediates-resistance-to-dna-damage-induced-apoptosis-by-modulating-foxo3a-localization-and-bcl-xl-deamidation


Share this

Usage statistics

142 total views
0 total downloads
These values cover views and downloads from WestminsterResearch and are for the period from September 2nd 2018, when this repository was created.