{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T05:06:30Z","timestamp":1790485590800,"version":"4.1.0"},"reference-count":111,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T00:00:00Z","timestamp":1619481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Myelofibrosis is a myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, bone marrow fibrosis, and a propensity towards transformation to acute leukemia. JAK inhibitors are the only approved therapy for myelofibrosis and have been successful in reducing spleen and symptom burden. However, they do not significantly impact disease progression and many patients are ineligible due to coexisting cytopenias. Patients who are refractory to JAK inhibition also have a dismal survival. Therefore, non-JAK inhibitor-based therapies are being explored in pre-clinical and clinical settings. In this review, we discuss novel treatments in development for myelofibrosis with targets outside of the JAK-STAT pathway. We focus on the mechanism, preclinical rationale, and available clinical efficacy and safety information of relevant agents including those that target apoptosis (navitoclax, KRT-232, LCL-161, imetelstat), epigenetic modulation (CPI-0610, bomedemstat), the bone marrow microenvironment (PRM-151, AVID-200, alisertib), signal transduction pathways (parsaclisib), and miscellaneous agents (tagraxofusp. luspatercept). We also provide commentary on the future of therapeutic development in myelofibrosis.<\/jats:p>","DOI":"10.3390\/cells10051034","type":"journal-article","created":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T21:18:20Z","timestamp":1619558300000},"page":"1034","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Next Generation Therapeutics for the Treatment of Myelofibrosis"],"prefix":"10.3390","volume":"10","author":[{"given":"Douglas","family":"Tremblay","sequence":"first","affiliation":[{"name":"Tisch Cancer Institute, Division of Hematology\/Oncology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1079, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Mascarenhas","sequence":"additional","affiliation":[{"name":"Tisch Cancer Institute, Division of Hematology\/Oncology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1079, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1002\/ajh.25230","article-title":"Primary myelofibrosis: 2019 update on diagnosis, risk-stratification and management","volume":"93","author":"Tefferi","year":"2018","journal-title":"Am. J. Hematol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Mesa, R., Miller, C.B., Thyne, M., Mangan, J., Goldberger, S., Fazal, S., Ma, X., Wilson, W., Paranagama, D.C., and Dubinski, D.G. (2016). Myeloproliferative neoplasms (MPNs) have a significant impact on patients\u2019 overall health and productivity: The MPN Landmark survey. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2208-2"},{"key":"ref_3","first-page":"121","article-title":"Myelofibrosis: Clinicopathologic features, prognosis, and management","volume":"16","author":"Harrison","year":"2018","journal-title":"Clin. Adv. Hematol. Oncol."},{"key":"ref_4","first-page":"e45","article-title":"Implications of Mutation Profiling in Myeloid Malignancies-PART 2: Myeloproliferative Neoplasms and Other Myeloid Malignancies","volume":"32","author":"Sokol","year":"2018","journal-title":"Oncology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3026","DOI":"10.1182\/blood-2008-06-158386","article-title":"Does primary myelofibrosis involve a defective stem cell niche? From concept to evidence","volume":"112","author":"Lataillade","year":"2008","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1016\/j.bbmt.2015.09.005","article-title":"Hematopoietic Cell Transplantation as Curative Therapy for Patients with Myelofibrosis: Long-Term Success in all Age Groups","volume":"21","author":"Deeg","year":"2015","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_7","unstructured":"United States Food and Drug Administration (2011). JAKAFI (Ruxolitinib) Label."},{"key":"ref_8","unstructured":"United States Food and Drug Administration (2019). INREBIC (Fedratinib) Label."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.ccr.2008.02.009","article-title":"Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera","volume":"13","author":"Wernig","year":"2008","journal-title":"Cancer Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1056\/NEJMoa1110557","article-title":"A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis","volume":"366","author":"Verstovsek","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1056\/NEJMoa1110556","article-title":"JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis","volume":"366","author":"Harrison","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e317","DOI":"10.1016\/S2352-3026(17)30088-1","article-title":"Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): A single-arm, open-label, non-randomised, phase 2, multicentre study","volume":"4","author":"Harrison","year":"2017","journal-title":"Lancet Haematol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1001\/jamaoncol.2015.1590","article-title":"Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial","volume":"1","author":"Pardanani","year":"2015","journal-title":"JAMA Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/nrc2210","article-title":"Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders","volume":"7","author":"Levine","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s13045-017-0417-z","article-title":"Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial","volume":"10","author":"Verstovsek","year":"2017","journal-title":"J. Hematol. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1038\/leu.2016.148","article-title":"Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis","volume":"30","author":"Harrison","year":"2016","journal-title":"Leukemia"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41467-019-13892-x","article-title":"Single-cell analysis based dissection of clonality in myelofibrosis","volume":"11","author":"Mylonas","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.6004\/jnccn.2017.0157","article-title":"NCCN Guidelines Insights: Myeloproliferative Neoplasms, Version 2.2018","volume":"15","author":"Mesa","year":"2017","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1182\/blood-2019-129288","article-title":"Fedratinib Induces Spleen Responses and Reduces Symptom Burden in Patients with Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis (MF) and Low Platelet Counts, who were Either Ruxolitinib-Na\u00efve or were Previously Treated with Ruxolitinib","volume":"134","author":"Harrison","year":"2019","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"889","DOI":"10.2147\/TCRM.S258704","article-title":"Evaluating the Safety, Efficacy, and Therapeutic Potential of Momelotinib in the Treatment of Intermediate\/High-Risk Myelofibrosis: Evidence to Date","volume":"16","author":"Bassiony","year":"2020","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1182\/blood-2016-09-740092","article-title":"Momelotinib inhibits ACVR1\/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents","volume":"129","author":"Asshoff","year":"2017","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3844","DOI":"10.1200\/JCO.2017.73.4418","article-title":"SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naive Patients With Myelofibrosis","volume":"35","author":"Mesa","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e73","DOI":"10.1016\/S2352-3026(17)30237-5","article-title":"Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): A randomised, open-label, phase 3 trial","volume":"5","author":"Harrison","year":"2018","journal-title":"Lancet Haematol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1080\/17474086.2018.1500456","article-title":"Pacritinib to treat myelofibrosis patients with thrombocytopenia","volume":"11","author":"Tremblay","year":"2018","journal-title":"Expert Rev. Hematol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Mascarenhas, J., Hoffman, R., Talpaz, M., Gerds, A.T., Stein, B., Gupta, V., Szoke, A., Drummond, M., Pristupa, A., and Granston, T. (2018). Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis: A Randomized Clinical Trial. JAMA Oncol.","DOI":"10.1001\/jamaoncol.2017.5818"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5825","DOI":"10.1182\/bloodadvances.2020003314","article-title":"Determining the recommended dose of pacritinib: Results from the PAC203 dose-finding trial in advanced myelofibrosis","volume":"4","author":"Gerds","year":"2020","journal-title":"Blood Adv."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1080\/13696998.2020.1741381","article-title":"Patient characteristics and outcomes after ruxolitinib discontinuation in patients with myelofibrosis","volume":"23","author":"Mascarenhas","year":"2020","journal-title":"J. Med. Econ."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1007\/s00277-017-3194-4","article-title":"Between a rux and a hard place: Evaluating salvage treatment and outcomes in myelofibrosis after ruxolitinib discontinuation","volume":"97","author":"Kuykendall","year":"2018","journal-title":"Ann. Hematol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1182\/blood-2017-05-783225","article-title":"Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation","volume":"130","author":"Newberry","year":"2017","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1002\/cncr.32664","article-title":"Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis","volume":"126","author":"Palandri","year":"2020","journal-title":"Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0168-9525(00)89010-1","article-title":"Regulators of cell death","volume":"11","author":"Korsmeyer","year":"1995","journal-title":"TIG"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1756-8722-5-2","article-title":"Deregulation of apoptosis-related genes is associated with PRV1 overexpression and JAK2 V617F allele burden in Essential Thrombocythemia and Myelofibrosis","volume":"5","author":"Tognon","year":"2012","journal-title":"J. Hematol. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1016\/j.celrep.2013.10.038","article-title":"Combined targeting of JAK2 and Bcl-2\/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors","volume":"5","author":"Waibel","year":"2013","journal-title":"Cell Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4284","DOI":"10.1182\/blood-2010-04-279125","article-title":"Treatment with the Bcl-xL inhibitor ABT-737 in combination with interferon alpha specifically targets JAK2V617F-positive polycythemia vera hematopoietic progenitor cells","volume":"116","author":"Lu","year":"2010","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10978","DOI":"10.1111\/jcmm.15730","article-title":"Bcl-xL represents a therapeutic target in Philadelphia negative myeloproliferative neoplasms","volume":"24","author":"Petiti","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Pemmaraju, N., Garcia, J., Potluri, J., Holes, L., Harb, J., Jung, P., Hutti, J., Prchal, J., Verstovsek, S., and Harrison, C. (2020, January 5\u20138). The Addition of Navitoclax to Ruxolitinib Demonstrates Efficacy within Different High-Risk Populations in Patients with Relapsed\/Refractory Myelofibrosis. Proceedings of the ASH Annual Meeting, San Diego, CA, USA. Abstract 52.","DOI":"10.1182\/blood-2020-136938"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Owens, T.W., Gilmore, A.P., Streuli, C.H., and Foster, F.M. (2013). Inhibitor of Apoptosis Proteins: Promising Targets for Cancer Therapy. J. Carcinog Mutagen., S14.","DOI":"10.4172\/2157-2518.S14-004"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40164-019-0157-6","article-title":"The SMAC mimetic LCL-161 selectively targets JAK2(V617F) mutant cells","volume":"9","author":"Craver","year":"2020","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1182\/blood-2019-130046","article-title":"Final Results of Phase 2 Clinical Trial of LCL161, a Novel Oral SMAC Mimetic\/IAP Antagonist, for Patients with Intermediate to High Risk Myelofibrosis","volume":"134","author":"Pemmaraju","year":"2019","journal-title":"Blood"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.exphem.2010.03.005","article-title":"Interferon-alpha targets JAK2V617F-positive hematopoietic progenitor cells and acts through the p38 MAPK pathway","volume":"38","author":"Lu","year":"2010","journal-title":"Exp. Hematol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/nrc3430","article-title":"MDM2, MDMX and p53 in oncogenesis and cancer therapy","volume":"13","author":"Wade","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1182\/blood-2012-02-410712","article-title":"Combination treatment in vitro with Nutlin, a small-molecule antagonist of MDM2, and pegylated interferon-alpha 2a specifically targets JAK2V617F-positive polycythemia vera cells","volume":"120","author":"Lu","year":"2012","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1182\/blood-2013-11-536854","article-title":"The orally bioavailable MDM2 antagonist RG7112 and pegylated interferon alpha 2a target JAK2V617F-positive progenitor and stem cells","volume":"124","author":"Lu","year":"2014","journal-title":"Blood"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1182\/blood.2018893545","article-title":"Oral idasanutlin in patients with polycythemia vera","volume":"134","author":"Mascarenhas","year":"2019","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Mascarenhas, J., Higgins, B., Anders, D., Burbury, K., El-Galaly, T., Gerds, A., Gupta, V., Kovic, B., Maffioli, M., and Mesa, R. (2020, January 5\u20138). Safety and Efficacy of Idasanutlin in Patients (pts) with Hydroxyurea (HU)-Resistant\/Intolerant Polycythemia Vera (PV): Results of an International Phase II Study. Proceedings of the ASH Annual Meeting, San Diego, CA, USA. Abstract 479.","DOI":"10.1182\/blood-2020-135868"},{"key":"ref_46","unstructured":"Al-Ali, H., Delgado, R., Lange, A., Pluta, A., McLornan, D., Vachhani, P., Damaj, G., Jost, P., Rejt\u0151, L., and Hus, M. (2020, January 12). KRT-232, a first-in-class, murine double minute 2 inhibitor (MDM2I), for myelofibrosis (MF) relapsed or refractory (R\/R) to janus-associated kinase inhibitor (JAKI) treatment (TX). Proceedings of the EHA Annual Meeting, Virtual Conference, Held Online, Abstract S215."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/20974","article-title":"Structure and ligand of a histone acetyltransferase bromodomain","volume":"399","author":"Dhalluin","year":"1999","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"8758","DOI":"10.1073\/pnas.1433065100","article-title":"The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis","volume":"100","author":"Dey","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.cell.2012.02.013","article-title":"Histone recognition and large-scale structural analysis of the human bromodomain family","volume":"149","author":"Filippakopoulos","year":"2012","journal-title":"Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"11365","DOI":"10.1073\/pnas.1411701111","article-title":"Blockade of oncogenic IkappaB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors","volume":"111","author":"Ceribelli","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1038\/nature09589","article-title":"Suppression of inflammation by a synthetic histone mimic","volume":"468","author":"Nicodeme","year":"2010","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"29-43.e7","DOI":"10.1016\/j.ccell.2018.03.024","article-title":"Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms","volume":"33","author":"Kleppe","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_53","unstructured":"Talpaz, M., Rampal, R., Verstovsek, S., Harrison, C., Drummond, M.W., Kiladjian, J., Vannucchi, A., Kremyanskaya, M., Schiller, G., and Patriarca, A. (2020, January 6). CPI-0610, a Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, As Monotherapy in Advanced Myelofibrosis Patients Refractory\/Intolerant to JAK Inhibitor: Update from Phase 2 MANIFEST Study. Proceedings of the ASH Annual Meeting, Virtual Conference, Held Online, Abstract 2163."},{"key":"ref_54","unstructured":"Verstovsek, S., Mascarenhas, J., Kremyanskaya, M., Hoffman, R., Rampal, R., Gupta, V., Talpaz, M., Granacher, N., Leber, B., and Kiladjian, J. (2020, January 5). CPI-0610, Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, As \u201cAdd-on\u201d to Ruxolitinib, in Advanced Myelofibrosis Patients with Suboptimal Response: Update of MANIFEST Phase 2 Study. Proceedings of the ASH Annual Meeting, Virtual Conference, Held Online, Abstract 56."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Mascarenhas, J., Harrison, C., Patriarca, A., Devos, T., Palandri, F., Rampal, R., Mead, A., Kremyanskaya, M., Somervaille, T., and Wondergem, M. (2020, January 5). CPI-0610, a Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, in Combination with Ruxolitinib, in JAK-Inhibitor-Na\u00efve Myelofibrosis Patients: Update of MANIFEST Phase 2 Study. Proceedings of the ASH Annual Meeting, Virtual Conference, Held Online, Abstract 55.","DOI":"10.1182\/blood-2019-128211"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1038\/leu.2012.157","article-title":"Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation","volume":"26","author":"Sprussel","year":"2012","journal-title":"Leukemia"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e54","DOI":"10.1097\/HS9.0000000000000054","article-title":"LSD1 Inhibition Prolongs Survival in Mouse Models of MPN by Selectively Targeting the Disease Clone","volume":"2","author":"Jutzi","year":"2018","journal-title":"Hemasphere"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Yacoub, A., Pettit, K.M., Bradley, T.J., Gerds, A., Tartaczuch, M., Shortt, J., Curtin, N.J., Rossetti, J.M., Burbury, K., and Mead, A. (2020, January 5). A Phase 2 Study of the LSD1 Inhibitor IMG7289 (bomedemstat) for the Treatment of Advanced Myelofibrosis. Proceedings of the ASH Annual Meeting, Virtual Conference, Held Online.","DOI":"10.1182\/blood-2019-123244"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1358\/dnp.2010.23.5.1444206","article-title":"PRM-151 (recombinant human serum amyloid P\/pentraxin 2) for the treatment of fibrosis","volume":"23","author":"Duffield","year":"2010","journal-title":"Drug News Perspect"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5537","DOI":"10.4049\/jimmunol.171.10.5537","article-title":"Inhibition of fibrocyte differentiation by serum amyloid P","volume":"171","author":"Pilling","year":"2003","journal-title":"J. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Murray, L.A., Rosada, R., Moreira, A.P., Joshi, A., Kramer, M.S., Hesson, D.P., Argentieri, R.L., Mathai, S., Gulati, M., and Herzog, E.L. (2010). Serum amyloid P therapeutically attenuates murine bleomycin-induced pulmonary fibrosis via its effects on macrophages. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009683"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1001\/jama.2018.6129","article-title":"Effect of Recombinant Human Pentraxin 2 vs Placebo on Change in Forced Vital Capacity in Patients With Idiopathic Pulmonary Fibrosis: A Randomized Clinical Trial","volume":"319","author":"Raghu","year":"2018","journal-title":"JAMA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1182\/blood-2018-99-115362","article-title":"PRM-151 in Myelofibrosis: Efficacy and Safety in an Open Label Extension Study","volume":"132","author":"Verstovsek","year":"2018","journal-title":"Blood"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Verstovsek, S., Talpaz, M., Wadleigh, M., Palmer, J., Isidori, A., te Boekhorst, P., Savona, M., Gotlib, J., Hasserjian, R., and Pozdnyakova, O. (2019, January 15). A randomized, double blind phase 2 study of 3 different doses of prm-151 in patients with myelofibrosis who were previously treated with or ineligible for ruxolitinib: S828. Proceedings of the EHA 2019, Amsterdam, The Netherlands. abstract 3.","DOI":"10.1097\/01.HS9.0000561592.51072.9b"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1182\/blood-2006-12-064626","article-title":"Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis","volume":"110","author":"Ciurea","year":"2007","journal-title":"Blood"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1182\/blood-2008-04-146480","article-title":"TGF-beta as a candidate bone marrow niche signal to induce hematopoietic stem cell hibernation","volume":"113","author":"Yamazaki","year":"2009","journal-title":"Blood"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"15231","DOI":"10.1073\/pnas.0406771101","article-title":"Transforming growth factor beta-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 up-regulation","volume":"101","author":"Scandura","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2022","DOI":"10.1182\/blood.V96.6.2022","article-title":"Transforming growth factor-beta: Pleiotropic role in the regulation of hematopoiesis","volume":"96","author":"Fortunel","year":"2000","journal-title":"Blood"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1634\/stemcells.18-2-102","article-title":"Release from quiescence of primitive human hematopoietic stem\/progenitor cells by blocking their cell-surface TGF-beta type II receptor in a short-term in vitro assay","volume":"18","author":"Fortunel","year":"2000","journal-title":"Stem Cells"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1084\/jem.20030980","article-title":"Quantitative trait analysis reveals transforming growth factor-beta2 as a positive regulator of early hematopoietic progenitor and stem cell function","volume":"199","author":"Langer","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1182\/blood-2018-99-116474","article-title":"AVID200, a Potent Trap for TGF-\u03b2 Ligands Inhibits TGF-\u03b21 Signaling in Human Myelofibrosis","volume":"132","author":"Varricchio","year":"2018","journal-title":"Blood"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Mascarenhas, J., Kosiorek, H., Varricchio, L., Bhave, R., Kuykendall, A., Komrokji, R., Gerds, A., Palmer, J., Gabler, A., and Sandy, L. (2020, January 5). Rationale for and Results of a Phase I Study of the TGF-\u03b2 1\/3 Inhibitor AVID200 in Subjects with Myelofibrosis: MPN-RC 118 Trial. Proceedings of the ASH Annual Meeting, Virtual Conference, Held Online, Abstract 1254.","DOI":"10.1182\/blood-2020-140830"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1111\/j.1749-6632.2009.04569.x","article-title":"Complex and context dependent regulation of hematopoiesis by TGF-beta superfamily signaling","volume":"1176","author":"Soderberg","year":"2009","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/S0014-4827(02)00013-7","article-title":"Regulation of human erythropoiesis by activin A, BMP2, and BMP4, members of the TGFbeta family","volume":"282","author":"Bartholin","year":"2003","journal-title":"Exp. Cell Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/S0301-472X(00)00488-4","article-title":"Transforming growth factor inhibits erythropoiesis by blocking proliferation and accelerating differentiation of erythroid progenitors","volume":"28","author":"Zermati","year":"2000","journal-title":"Exp. Hematol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1182\/blood-2018-11-876888","article-title":"Luspatercept for the treatment of anemia in myelodysplastic syndromes and primary myelofibrosis","volume":"133","author":"Fenaux","year":"2019","journal-title":"Blood"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1038\/nm.3512","article-title":"Transforming growth factor-beta superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis","volume":"20","author":"Suragani","year":"2014","journal-title":"Nat. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1182\/blood-2019-122546","article-title":"A Phase 2 Study of Luspatercept in Patients with Myelofibrosis-Associated Anemia","volume":"134","author":"Gerds","year":"2019","journal-title":"Blood"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1182\/blood-2020-140441","article-title":"Sotatercept (ACE-011) for Anemia of Myelofibrosis: A Phase 2 Study","volume":"136","author":"Bose","year":"2020","journal-title":"Blood"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4369","DOI":"10.1182\/blood.V90.11.4369","article-title":"High thrombopoietin production by hematopoietic cells induces a fatal myeloproliferative syndrome in mice","volume":"90","author":"Villeval","year":"1997","journal-title":"Blood"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1182\/blood-2002-06-1913","article-title":"Development of myelofibrosis in mice genetically impaired for GATA-1 expression (GATA-1(low) mice)","volume":"100","author":"Vannucchi","year":"2002","journal-title":"Blood"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1182\/blood-2004-02-0419","article-title":"Megakaryocytes express functional Aurora-B kinase in endomitosis","volume":"104","author":"Geddis","year":"2004","journal-title":"Blood"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1038\/nm.3995","article-title":"Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition","volume":"21","author":"Wen","year":"2015","journal-title":"Nat. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"4898","DOI":"10.1158\/1078-0432.CCR-19-1005","article-title":"Aurora Kinase A Inhibition Provides Clinical Benefit, Normalizes Megakaryocytes, and Reduces Bone Marrow Fibrosis in Patients with Myelofibrosis: A Phase I Trial","volume":"25","author":"Gangat","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"S307","DOI":"10.1016\/j.clml.2013.07.011","article-title":"Rationale for targeting the PI3K\/Akt\/mTOR pathway in myeloproliferative neoplasms","volume":"13","author":"Bartalucci","year":"2013","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"954","DOI":"10.18632\/oncotarget.652","article-title":"Mutations and deregulation of Ras\/Raf\/MEK\/ERK and PI3K\/PTEN\/Akt\/mTOR cascades which alter therapy response","volume":"3","author":"McCubrey","year":"2012","journal-title":"Oncotarget"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1111\/j.1365-2141.2009.07870.x","article-title":"Phospho-STAT5 and phospho-Akt expression in chronic myeloproliferative neoplasms","volume":"147","author":"Grimwade","year":"2009","journal-title":"Br. J. Haematol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1038\/nature03546","article-title":"A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera","volume":"434","author":"James","year":"2005","journal-title":"Nature"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Bogani, C., Bartalucci, N., Martinelli, S., Tozzi, L., Guglielmelli, P., Bosi, A., Vannucchi, A.M., and on behalf of the Associazione Italiana per la Ricerca sul Cancro AGIMM Gruppo Italiano Malattie Mieloproliferative (2013). mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0054826"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.1182\/blood-2011-01-330563","article-title":"Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1\/2 study in patients with myelofibrosis","volume":"118","author":"Guglielmelli","year":"2011","journal-title":"Blood"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e551","DOI":"10.3324\/haematol.2018.209965","article-title":"Results from HARMONY: An open-label, multicenter, 2-arm, phase 1b, dose-finding study assessing the safety and efficacy of the oral combination of ruxolitinib and buparlisib in patients with myelofibrosis","volume":"104","author":"Durrant","year":"2019","journal-title":"Haematologica"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1158\/2159-8290.CD-11-0249","article-title":"PI3Kdelta inhibitors in cancer: Rationale and serendipity merge in the clinic","volume":"1","author":"Fruman","year":"2011","journal-title":"Cancer Discov."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Yacoub, A., Wang, E., Rampal, R., Borate, U., Kremyanskaya, M., Ali, H., Hobbs, G., O\u2019Connell, C., Assad, A., and Erickson-Viitanen, S. (2020, January 12). Addition of parsaclisib, a pi3kdelta inhibitor, in patients (PTS) with suboptimal response to ruxolitinib (RUX): A Phase 2 study in pts with myelofibrosis (MF). Proceedings of the EHA Annual Meeting, Virtual Conference, Held Online, Abstract S216.","DOI":"10.1158\/1538-7445.AM2021-CT162"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1038\/sj.leu.2401903","article-title":"The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells","volume":"14","author":"Jordan","year":"2000","journal-title":"Leukemia"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/2050-7771-2-4","article-title":"CD 123 is a membrane biomarker and a therapeutic target in hematologic malignancies","volume":"2","author":"Testa","year":"2014","journal-title":"Biomark Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.1056\/NEJMoa1815105","article-title":"Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm","volume":"380","author":"Pemmaraju","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"5577","DOI":"10.1182\/blood.V124.21.5577.5577","article-title":"Expression of CD123 (IL-3R-alpha), a Therapeutic Target of SL-401, on Myeloproliferative Neoplasms","volume":"124","author":"Lasho","year":"2014","journal-title":"Blood"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1200\/JCO.2010.32.2446","article-title":"DIPSS plus: A refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status","volume":"29","author":"Gangat","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1182\/blood-2019-131217","article-title":"Results from a Phase 1\/2 Clinical Trial of Tagraxofusp (SL-401) in Patients with Intermediate, or High Risk, Relapsed\/Refractory Myelofibrosis","volume":"134","author":"Pemmaraju","year":"2019","journal-title":"Blood"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/0092-8674(89)90035-4","article-title":"The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats","volume":"59","author":"Morin","year":"1989","journal-title":"Cell"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1126\/science.7605428","article-title":"Specific association of human telomerase activity with immortal cells and cancer","volume":"266","author":"Kim","year":"1994","journal-title":"Science"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.exphem.2013.03.007","article-title":"Telomere shortening in Ph-negative chronic myeloproliferative neoplasms: A biological marker of polycythemia vera and myelofibrosis, regardless of hydroxycarbamide therapy","volume":"41","author":"Ruella","year":"2013","journal-title":"Exp. Hematol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"5262","DOI":"10.1038\/sj.onc.1208760","article-title":"Lipid modification of GRN163, an N3\u2032-->P5\u2032 thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibition","volume":"24","author":"Herbert","year":"2005","journal-title":"Oncogene"},{"key":"ref_104","first-page":"221","article-title":"Imetelstat (GRN163L)--telomerase-based cancer therapy","volume":"184","author":"Roth","year":"2010","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1056\/NEJMoa1310523","article-title":"A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis","volume":"373","author":"Tefferi","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_106","unstructured":"Mascarenhas, J., Komrokji, R., Cavo, M., Martino, B., Niederwieser, D., Reiter, A., Scott, B., Baer, M., Hoffman, R., and Odenike, O. (2020, January 6). Favorable Overall Survival with Imetelstat Treatment Correlates with Other Clinical Benefits in Intermediate 2 or High Risk Myelofibrosis Relapsed\/Refractory to Janus Kinase Inhibitor. Proceedings of the ASH Annual Meeting, Virtual Conference, Held Online, Abstract 53."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Mascarenhas, J., Komrokji, R., Cavo, M., Martino, B., Niederwieser, D., Reiter, A., Scott, B., Baer, M., Hoffman, R., and Odenike, O. (2020, January 5). Correlation Analyses of Imetelstat Exposure with Pharmacodynamic Effect, Efficacy and Safety in a Phase 2 Study in Patients with Higher-Risk Myelofibrosis Refractory to Janus Kinase Inhibitor Identified an Optimal Dosing Regimen for Phase 3 Study. Proceedings of the ASH Annual Meeting, Virtual Conference, Held Online, Abstract 1283.","DOI":"10.1182\/blood-2020-138905"},{"key":"ref_108","unstructured":"Mascarenhas, J., Komrokji, R., Cavo, M., Martino, B., Niederwieser, D., Reiter, A., Scott, B., Baer, M., Hoffman, R., and Odenike, O. (2020, January 6). Telomerase Activity, Telomere Length and hTERT Expression Correlate with Clinical Outcomes in Higher-Risk Myelofibrosis (MF) Relapsed\/Refractory (R\/R) to Janus Kinase Inhibitor Treated with Imetelstat. Proceedings of the ASH Annual Meeting, Virtual Conference, Held Online, Abstract 347."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1111\/ejh.13005","article-title":"Significance of thrombocytopenia in patients with primary and postessential thrombocythemia\/polycythemia vera myelofibrosis","volume":"100","author":"Masarova","year":"2018","journal-title":"Eur. J. Haematol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"167","DOI":"10.3324\/haematol.2010.031831","article-title":"Red blood cell transfusion-dependency implies a poor survival in primary myelofibrosis irrespective of IPSS and DIPSS","volume":"96","author":"Elena","year":"2011","journal-title":"Haematologica"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1002\/cncr.30325","article-title":"Differences in treatment goals and perception of symptom burden between patients with myeloproliferative neoplasms (MPNs) and hematologists\/oncologists in the United States: Findings from the MPN Landmark survey","volume":"123","author":"Mesa","year":"2017","journal-title":"Cancer"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/5\/1034\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:53:32Z","timestamp":1760162012000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/5\/1034"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,27]]},"references-count":111,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["cells10051034"],"URL":"https:\/\/doi.org\/10.3390\/cells10051034","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,27]]}}}