Wild-type p53-induced phosphatase sensitizes acute myeloid leukemia cells to conventional chemotherapy

Authors

  • Vasily Golotin Laboratory of Molecular Medicine, Institute of Cytology of the Russian Academy of Sciences, Tikhoretskiy pr., 4, Saint Petersburg, 194064, Russian Federation https://orcid.org/0000-0003-0385-2463
  • Ekaterina Belotserkovskaya Almazov Federal Medical Research Centre, ul. Akkuratova, 2, 197341, Saint Petersburg, Russian Federation https://orcid.org/0000-0003-3985-9552
  • Larisa Girshova Almazov Federal Medical Research Centre, ul. Akkuratova, 2, 197341, Saint Petersburg, Russian Federation https://orcid.org/0000-0002-0559-9556
  • Alexey Petukhov Almazov Federal Medical Research Centre, ul. Akkuratova, 2, 197341, Saint Petersburg, Russian Federation https://orcid.org/0000-0002-7298-5238
  • Andrey Zaritsky Almazov Federal Medical Research Centre, ul. Akkuratova, 2, 197341, Saint Petersburg, Russian Federation
  • Oleg Demidov Laboratory of Molecular Medicine, Institute of Cytology of the Russian Academy of Sciences, Tikhoretskiy pr., 4, Saint Petersburg, 194064, Russian Federation; INSERM UMR1231, Laboratory of Excellence LipSTIC and label Ligue Nationale contre le Cancer, 7 Boulevard Jeanne d'Arc, BP 27877, 21078, Dijon Cedex, France https://orcid.org/0000-0003-4323-7174

DOI:

https://doi.org/10.21638/spbu03.2021.308

Abstract

Recently wild-type p53-induced phosphatase was implicated in the pathogenesis of acute myeloid leukemia (AML) and “pre-leukemia” myeloproliferative conditions. Here we decided to check how the strategy directed to phosphatase inhibition affected sensitivity to conventional chemotherapy. All experiments were conducted on AML cell lines cultivated in vitro. The levels of wild-type p53-induced phosphatase vary in different AML cell lines. The chemical compound GSK2830371 reduced levels of phosphatase and diminished its activity. GSK2830371 did not significantly change the cell cycle distribution of AML cells when used alone or in combination with the anti-cancer chemotherapeutic drug Cytosar but increased caspase-dependent PARP1 cleavage. In contrast with previous studies, we did not observe the negative effect of phosphatase activity inhibition and depletion on cells when a chemical inhibitor was used as monotherapy. Using a combination of GSK2830371 with Cytosar we were able to reduce the threshold of chemotherapy-dependent cytotoxicity and more efficiently eliminate leukemic cells. We propose considering inhibition of wild-type p53-induced phosphatase as a prospective strategy in improving anti-AML therapy.

Keywords:

leukemia, AML, chemotherapy, cytarabine

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References

Cai, S. F. and Levine, R. L. 2019. Genetic and epigenetic determinants of AML pathogenesis. Seminars in Hematology 56(2):84–89. https://doi.org/10.1053/j.seminhematol.2018.08.001

Genovese, G., Kähler, A. K., Handsaker, R. E., Lindberg, J., Rose, S. A., Bakhoum, S. F., Chambert, K., Mick, E., Neale, B. M., Fromer, M., Purcell, S. M., Svantesson, O., Landén, M., Höglund, M., Lehmann, S., Gabriel, S. B., Moran, J. L., Lander, E. S., Sullivan, P. F., Sklar, P., Grönberg, H., Hultman, C. M., and McCarroll, S. A. 2014. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. The New England Journal of Medicine 371(26):2477–2487. https://doi.org/10.1056/NEJMoa1409405

Hsu, J. I., Dayaram, T., Tovy, A., De Braekeleer, E., Jeong, M., Wang, F., Zhang, J., Heffernan, T. P., Gera, S., Kovacs, J. J., Marszalek, J. R., Bristow, C., Yan, Y., Garcia-Manero, G., Kantarjian, H., Vassiliou, G., Futreal, P. A., Donehower, L. A., Takahashi, K., and Goodell, M. A. 2018. PPM1D mutations drive clonal hematopoiesis in response to cytotoxic chemotherapy. Cell Stem Cell 23(5):700–713. https://doi.org/10.1016/j.stem.2018.10.004

Kartal-Kaess, M., Bochtler, T., Kraft, B., Kirsch, M., Maier, B., Stoelzel, F., Mohr, B., Kramer, M., Rollig, C., Thiede, C., Bornhäuser, M., Ehninger, G., Müller-Tidow, C., and Krämer, A. 2018. PPM1D mutations are rare in de novo and therapy-related acute myeloid leukemia. Blood 132(Suppl. 1):1472. https://doi.org/10.1182/blood-2018-99-118566

Li, B., Hu, J., He, D., Chen, Q., Liu, S., Zhu, X., and Yu, M. 2020. PPM1D knockdown suppresses cell proliferation, promotes cell apoptosis, and activates p38 MAPK/p53 signaling pathway in acute myeloid leukemia. Technology in Cancer Research and Treatment 19:1533033820942312. https://doi.org/10.1177/1533033820942312

Lindsley, R. C., Saber, W., Mar, B. G., Redd, R., Wang, T., Haagenson, M. D., Grauman, P. V., Hu, Z. H., Spellman, S. R., Lee, S. J., Verneris, M. R., Hsu, K., Fleischhauer, K., Cutler, C., Antin, J. H., Neuberg, D., and Ebert, B. L. 2017. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. The New England Journal of Medicine 376:536–547. https://doi.org/10.1056/NEJMoa1611604

Lu, X., Nannenga, B., and Donehower, L. A. 2005. PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. Genes and Development 19(10):1162–1174. https://doi.org/10.1101/gad.1291305

Mesa, R. A., Loegering, D., Powell, H. L, Flatten, K., Arlander, S. J., Dai, N. T., Heldebrant, M. P., Vroman, B. T., Smith, B. D., Karp, J. E., Eyck, C. J., Erlichman, C., Kaufmann, S. H., and Karnitz, L. M. 2005. Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine. Blood 106(1):318–327. https://doi.org/10.1182/blood-2004-09-3523

Motomura, M., Inoue, Y., Nagata, Y., Yoshizato, T., Baer, C., Momozawa, Y., Nadarajah, N., Nannya, Y., Yoshida, K., Haferlach, C., Kern, W., Atsuta, Y., Iijima-Yamashita, Y., Shiraishi, Y., Onizuka, M., Chiba, K., Tanaka, H., Itonaga, H., Miyazaki, Y., Horibe, K., Sanada, M., Kamatani, Y., Kubo, M., Miyano, S., Haferlach, T., Ogawa, S., and Makishima, H. 2019. PPM1D and DNMT3A mutations in myelodysplasia and clonal hematopoiesis. Blood 134(Suppl.1):1709. https://doi.org/10.1182/blood-2019-122032

Rossi, M., Demidov, O. N., Anderson, C. W., Appella, E., and Mazur, S. J. 2008. Induction of PPM1D following DNA-damaging treatments through a conserved p53 response element coincides with a shift in the use of transcription initiation sites. Nucleic Acids Research 36(22):7168–7180. https://doi.org/10.1093/nar/gkn888

Yu, M., Hu, J., He, D., Chen, Q., Liu, S., Zhu, X., and Li, B. 2020. Potentiality of protein phosphatase Mg2+, Mn2+ - dependent 1D as a biomarker for predicting prognosis in acute myeloid leukemia patients. Journal of Clinical Laboratory Analysis 34(5):e23171. https://doi.org/10.1002/jcla.23171

Uyanik, B., Grigorash, B. B., Goloudina, A. R., and Demidov, O. N. 2017. DNA damage-induced phosphatase Wip1 in regulation of hematopoiesis, immune system and inflammation. Cell Death Discovery 3:17018. https://doi.org/10.1038/cddiscovery.2017.18

Biological Communications

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Published

2021-11-12

How to Cite

Golotin, V., Belotserkovskaya, E., Girshova, L., Petukhov, A., Zaritsky, A., & Demidov, O. (2021). Wild-type p53-induced phosphatase sensitizes acute myeloid leukemia cells to conventional chemotherapy. Biological Communications, 66(3), 268–273. https://doi.org/10.21638/spbu03.2021.308

Issue

Vol. 66 No. 3 (2021)

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Brief communications

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Articles of Biological Communications are open access distributed under the terms of the License Agreement with Saint Petersburg State University, which permits to the authors unrestricted distribution and self-archiving free of charge.