Understanding Aberrant Signaling to Elude Therapy Escape Mechanisms in Myeloproliferative Neoplasms

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2022 Feb 25

PMID 35205715

Authors

Maria Teresa Bochicchio

Valeria Di Battista

Pietro Poggio

Giovanna Carra

Alessandro Morotti

Mara Brancaccio

Alessandro Lucchesi

Affiliations

Soon will be listed here.

Abstract

Aberrant signaling in myeloproliferative neoplasms may arise from alterations in genes coding for signal transduction proteins or epigenetic regulators. Both mutated and normal cells cooperate, altering fragile balances in bone marrow niches and fueling persistent inflammation through paracrine or systemic signals. Despite the hopes placed in targeted therapies, myeloid proliferative neoplasms remain incurable diseases in patients not eligible for stem cell transplantation. Due to the emergence of drug resistance, patient management is often very difficult in the long term. Unexpected connections among signal transduction pathways highlighted in neoplastic cells suggest new strategies to overcome neoplastic cell adaptation.

References

Pikman Y, Lee B, Mercher T, McDowell E, Ebert B, Gozo M . MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006; 3(7):e270. PMC: 1502153. DOI: 10.1371/journal.pmed.0030270. View

Lu M, Xia L, Li Y, Wang X, Hoffman R . The orally bioavailable MDM2 antagonist RG7112 and pegylated interferon α 2a target JAK2V617F-positive progenitor and stem cells. Blood. 2014; 124(5):771-9. PMC: 4467881. DOI: 10.1182/blood-2013-11-536854. View

Chen W, Nyuydzefe M, Weiss J, Zhang J, Waksal S, Zanin-Zhorov A . ROCK2, but not ROCK1 interacts with phosphorylated STAT3 and co-occupies TH17/TFH gene promoters in TH17-activated human T cells. Sci Rep. 2018; 8(1):16636. PMC: 6226480. DOI: 10.1038/s41598-018-35109-9. View

Mondello P, Cuzzocrea S, Mian M . Pim kinases in hematological malignancies: where are we now and where are we going?. J Hematol Oncol. 2014; 7:95. PMC: 4266197. DOI: 10.1186/s13045-014-0095-z. View

Marit M, Chohan M, Matthew N, Huang K, Kuntz D, Rose D . Random mutagenesis reveals residues of JAK2 critical in evading inhibition by a tyrosine kinase inhibitor. PLoS One. 2012; 7(8):e43437. PMC: 3420867. DOI: 10.1371/journal.pone.0043437. View

Kim H, Kim D, Choi S, Rok Kim C, Oh S, Pyo K . KDM3A histone demethylase functions as an essential factor for activation of JAK2-STAT3 signaling pathway. Proc Natl Acad Sci U S A. 2018; 115(46):11766-11771. PMC: 6243239. DOI: 10.1073/pnas.1805662115. View

Girodon F, Steinkamp M, Cleyrat C, Hermouet S, Wilson B . Confocal imaging studies cast doubt on nuclear localization of JAK2V617F. Blood. 2011; 118(9):2633-4. PMC: 4131456. DOI: 10.1182/blood-2011-02-336479. View

Wang Y, Zuo X . Cytokines frequently implicated in myeloproliferative neoplasms. Cytokine X. 2021; 1(1):100005. PMC: 7885877. DOI: 10.1016/j.cytox.2019.100005. View

Wang J, Chen C, Dumlao T, Naik S, Chang T, Xiao Y . Enhanced histone deacetylase enzyme activity in primary myelofibrosis. Leuk Lymphoma. 2008; 49(12):2321-7. DOI: 10.1080/10428190802527699. View

10.

James C, Ugo V, Le Couedic J, Staerk J, Delhommeau F, Lacout C . A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005; 434(7037):1144-8. DOI: 10.1038/nature03546. View

11.

Bhagwat N, Levine R, Koppikar P . Sensitivity and resistance of JAK2 inhibitors to myeloproliferative neoplasms. Int J Hematol. 2013; 97(6):695-702. DOI: 10.1007/s12185-013-1353-5. View

12.

Tefferi A, Barbui T . Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management. Am J Hematol. 2018; 94(1):133-143. DOI: 10.1002/ajh.25303. View

13.

Deshpande A, Reddy M, Schade G, Ray A, Chowdary T, Griffin J . Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms. Leukemia. 2011; 26(4):708-15. PMC: 3974504. DOI: 10.1038/leu.2011.255. View

14.

Stivala S, Codilupi T, Brkic S, Baerenwaldt A, Ghosh N, Hao-Shen H . Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms. J Clin Invest. 2019; 129(4):1596-1611. PMC: 6436863. DOI: 10.1172/JCI98785. View

15.

Gastinne T, Vigant F, Lavenu-Bombled C, Wagner-Ballon O, Tulliez M, Chagraoui H . Adenoviral-mediated TGF-beta1 inhibition in a mouse model of myelofibrosis inhibit bone marrow fibrosis development. Exp Hematol. 2007; 35(1):64-74. DOI: 10.1016/j.exphem.2006.08.016. View

16.

Vannucchi A, Lasho T, Guglielmelli P, Biamonte F, Pardanani A, Pereira A . Mutations and prognosis in primary myelofibrosis. Leukemia. 2013; 27(9):1861-9. DOI: 10.1038/leu.2013.119. View

17.

Winter P, Sarosiek K, Lin K, Meggendorfer M, Schnittger S, Letai A . RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis. Sci Signal. 2014; 7(357):ra122. PMC: 4353591. DOI: 10.1126/scisignal.2005301. View

18.

Solimani F, Meier K, Ghoreschi K . Emerging Topical and Systemic JAK Inhibitors in Dermatology. Front Immunol. 2019; 10:2847. PMC: 6901833. DOI: 10.3389/fimmu.2019.02847. View

19.

Harrison C, Vannucchi A, Kiladjian J, Al-Ali H, Gisslinger H, Knoops L . Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016; 30(8):1701-7. PMC: 5399157. DOI: 10.1038/leu.2016.148. View

20.

Tefferi A, Vaidya R, Caramazza D, Finke C, Lasho T, Pardanani A . Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. J Clin Oncol. 2011; 29(10):1356-63. DOI: 10.1200/JCO.2010.32.9490. View