{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T12:01:41Z","timestamp":1774008101992,"version":"3.50.1"},"reference-count":52,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Stem cells, also known as progenitor cells, can differentiate into specialized cells for specific tissues. Genetic mutations and epigenetic changes may cause normal stem cells to become cancer-initiating cells. Research indicates that cells acquiring a mutation for myeloproliferative neoplasm (MPN) are likely to be long-term hematopoietic stem cells (LT-HSCs) at the top of the hematopoietic hierarchy. Natural killer (NK) cells play a crucial role in combating cancer by targeting and eliminating cancer stem cells (CSCs) while promoting their maturation. NK cells do this through direct lysis of CSCs or by releasing cytokines like interferon-gamma (IFN-\u03b3) and tumor necrosis factor-alpha (TNF-\u03b1), which inhibit tumor growth and metastasis by driving differentiation of CSCs. Interleukin-2 (IL-2) enhances the activity of CD4+ and CD8+ T cells and boosts NK cell cytotoxicity. This study highlights a case of MPN with a more clinically aggressive Type 1 calreticulin (CALR) mutation, where a combination of low-dose IL-2 immunotherapy and targeted therapy with oral tretinoin (all-trans retinoic acid, ATRA, a vitamin A derivative) improved immune cells, particularly NK-cell-mediated destruction of malignant cells, reduced CALR mutation levels to undetectable, and alleviated disease symptoms. The aim is to offer a new, low-toxicity personalized treatment strategy that eradicates cancer-initiating stem cells, reduces side effects, and provides an option for patients with limited conventional therapy alternatives.<\/jats:p>","DOI":"10.3390\/ijms27062814","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T09:44:41Z","timestamp":1773999881000},"page":"2814","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Interleukin-2 and Tretinoin for Myeloproliferative Neoplasms and to Target Type 1 Calreticulin-Driven Neoplasms: Advancements in Immune Regenerative Medicine"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9825-1905","authenticated-orcid":false,"given":"Dipnarine","family":"Maharaj","sequence":"first","affiliation":[{"name":"The Maharaj Institute of Immune Regenerative Medicine, Boynton Beach, FL 33437, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Maharaj Institute of Immune Regenerative Medicine, Boynton Beach, FL 33437, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1936-5985","authenticated-orcid":false,"given":"Kawaljit","family":"Kaur","sequence":"additional","affiliation":[{"name":"ImmuneLink, LLC, Riverside, CA 92508, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacqueline","family":"Gouvea","sequence":"additional","affiliation":[{"name":"The Maharaj Institute of Immune Regenerative Medicine, Boynton Beach, FL 33437, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100172","DOI":"10.1016\/j.bea.2025.100172","article-title":"Stem cells in regenerative medicine: Unlocking therapeutic potential through stem cell therapy, 3D bioprinting, gene editing, and drug discovery","volume":"9","author":"Sadiq","year":"2025","journal-title":"Biomed. Eng. Adv."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15283\/ijsc19127","article-title":"Hematopoietic Stem Cells and Their Roles in Tissue Regeneration","volume":"13","author":"Lee","year":"2020","journal-title":"Int. J. Stem Cells"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6224","DOI":"10.1073\/pnas.0601462103","article-title":"The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation","volume":"103","author":"Jamieson","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3128","DOI":"10.1182\/blood-2006-04-017392","article-title":"Involvement of various hematopoietic-cell lineages by the JAK2V617F mutation in polycythemia vera","volume":"108","author":"Ishii","year":"2006","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1182\/blood-2006-03-007146","article-title":"Evidence that the JAK2 G1849T (V617F) mutation occurs in a lymphomyeloid progenitor in polycythemia vera and idiopathic myelofibrosis","volume":"109","author":"Delhommeau","year":"2007","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1038\/nature04980","article-title":"Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9","volume":"442","author":"Krivtsov","year":"2006","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.ccr.2010.12.012","article-title":"Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia","volume":"19","author":"Goardon","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1038\/nm.4103","article-title":"A humanized bone marrow ossicle xenotransplantation model enables improved engraftment of healthy and leukemic human hematopoietic cells","volume":"22","author":"Reinisch","year":"2016","journal-title":"Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1182\/blood-2012-01-402396","article-title":"Distinct roles for long-term hematopoietic stem cells and erythroid precursor cells in a murine model of Jak2V617F-mediated polycythemia vera","volume":"120","author":"Mullally","year":"2012","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Spivak, J.L., and Moliterno, A.R. (2021). The Thrombopoietin Receptor, MPL, Is a Therapeutic Target of Opportunity in the MPN. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.641613"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"a034876","DOI":"10.1101\/cshperspect.a034876","article-title":"The Molecular Genetics of Myeloproliferative Neoplasms","volume":"10","author":"Marneth","year":"2020","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.1182\/blood.2022017416","article-title":"Biology and therapeutic targeting of molecular mechanisms in MPNs","volume":"141","author":"How","year":"2023","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1182\/blood.2022017578","article-title":"Genetic basis and molecular profiling in myeloproliferative neoplasms","volume":"141","author":"Kralovics","year":"2023","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bel\u010di\u010d Miki\u010d, T., Paji\u010d, T., Zver, S., and Sever, M. (2021). The Contemporary Approach to CALR-Positive Myeloproliferative Neoplasms. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073371"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/leu.2015.277","article-title":"Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms","volume":"30","author":"Pietra","year":"2016","journal-title":"Leukemia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/s41422-020-0383-9","article-title":"Calreticulin and cancer","volume":"31","author":"Fucikova","year":"2021","journal-title":"Cell Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1007\/s12672-025-02198-8","article-title":"Advancements and limitations in traditional anti-cancer therapies: A comprehensive review of surgery, chemotherapy, radiation therapy, and hormonal therapy","volume":"16","author":"Zafar","year":"2025","journal-title":"Discov. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.2217\/fon-2023-0513","article-title":"The impact of myelosuppression on quality of life of patients treated with chemotherapy","volume":"20","author":"Crawford","year":"2024","journal-title":"Future Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1182\/blood.V89.7.2303","article-title":"Radiotherapy-Associated Neutropenia and Thrombocytopenia: Analysis of Risk Factors and Development of a Predictive Model","volume":"89","author":"Lamborn","year":"1997","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1002\/ajh.27660","article-title":"Allogeneic Stem Cell Transplant for Myelofibrosis and Myelodysplastic Syndromes: A Contemporary Review","volume":"100","author":"Gagelmann","year":"2025","journal-title":"Am. J. Hematol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41408-020-00392-1","article-title":"Ruxolitinib discontinuation syndrome: Incidence, risk factors, and management in 251 patients with myelofibrosis","volume":"11","author":"Palandri","year":"2021","journal-title":"Blood Cancer J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"128","DOI":"10.3810\/pgm.2013.01.2628","article-title":"Ruxolitinib: An oral Janus kinase 1 and Janus kinase 2 inhibitor in the management of myelofibrosis","volume":"125","author":"Verstovsek","year":"2013","journal-title":"Postgrad. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1182\/hematology.2024000577","article-title":"Pegylated interferon: The who, why, and how","volume":"2024","author":"Kiladjian","year":"2024","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2585","DOI":"10.1182\/blood-2015-07-659060","article-title":"Clinical and molecular response to interferon-\u03b1 therapy in essential thrombocythemia patients with CALR mutations","volume":"126","author":"Verger","year":"2015","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e52904","DOI":"10.15252\/embr.202152904","article-title":"Targeting human CALR-mutated MPN progenitors with a neoepitope-directed monoclonal antibody","volume":"23","author":"Tvorogov","year":"2022","journal-title":"EMBO Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"100652","DOI":"10.1016\/j.oor.2024.100652","article-title":"Current advances in immunotherapy for cancer","volume":"12","author":"Desai","year":"2024","journal-title":"Oral. Oncol. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1182\/blood-2024-204953","article-title":"Development of a First-in-Class CAR-T Therapy Against Calreticulin-Mutant Neoplasms and Evaluation in the Relevant Human Tissue Environment","volume":"144","author":"Rampotas","year":"2024","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1007\/s11899-024-00749-4","article-title":"Mutant Calreticulin in MPN: Mechanistic Insights and Therapeutic Implications","volume":"20","author":"Faiz","year":"2025","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e658","DOI":"10.1016\/S2352-3026(21)00204-0","article-title":"Unmet clinical needs in the management of CALR-mutated essential thrombocythaemia: A consensus-based proposal from the European LeukemiaNet","volume":"8","author":"Harrison","year":"2021","journal-title":"Lancet Haematol."},{"key":"ref_30","first-page":"241","article-title":"Impact of calreticulin mutations on treatment and survival outcomes in myelofibrosis during ruxolitinib therapy","volume":"104","author":"Palandri","year":"2025","journal-title":"Ann. Hematol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/s12964-023-01302-1","article-title":"Unveiling the mechanisms and challenges of cancer drug resistance","volume":"22","author":"Khan","year":"2024","journal-title":"Cell Commun. Signal"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Szyma\u0144ski, \u0141., Skopek, R., Palusi\u0144ska, M., Schenk, T., Stengel, S., Lewicki, S., Kraj, L., Kami\u0144ski, P., and Zelent, A. (2020). Retinoic Acid and Its Derivatives in Skin. Cells, 9.","DOI":"10.3390\/cells9122660"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1016\/j.ccell.2025.03.008","article-title":"All-trans retinoic acid beyond acute promyelocytic leukemia","volume":"43","author":"Rehman","year":"2025","journal-title":"Cancer Cell"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Garg, P., Pareek, S., Kulkarni, P., Horne, D., Salgia, R., and Singhal, S.S. (2024). Next-Generation Immunotherapy: Advancing Clinical Applications in Cancer Treatment. J. Clin. Med., 13.","DOI":"10.3390\/jcm13216537"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"155916","DOI":"10.1016\/j.cyto.2022.155916","article-title":"Cytokine chemokine network in tumor microenvironment: Impact on CSC properties and therapeutic applications","volume":"156","author":"Nengroo","year":"2022","journal-title":"Cytokine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.molmed.2025.01.010","article-title":"Engineering cytokines for tumor-targeting and selective T cell activation","volume":"31","author":"Peng","year":"2025","journal-title":"Trends Mol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1038\/s41423-020-0481-0","article-title":"Cytokines that target immune killer cells against tumors","volume":"17","author":"Qiao","year":"2020","journal-title":"Cell Mol. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1186\/s40001-024-01711-z","article-title":"The paradoxical role of cytokines and chemokines at the tumor microenvironment: A comprehensive review","volume":"29","author":"Ghosh","year":"2024","journal-title":"Eur. J. Med. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1089\/jir.2018.0019","article-title":"Cytokines in the Treatment of Cancer","volume":"39","author":"Conlon","year":"2019","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"101240","DOI":"10.1016\/j.ecoser.2020.101240","article-title":"Challenges and opportunities to scale up sustainable finance after the COVID-19 crisis: Lessons and promising innovations from science and practice","volume":"48","author":"Quatrini","year":"2021","journal-title":"Ecosyst. Serv."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Mortara, L., Balza, E., Bruno, A., Poggi, A., Orecchia, P., and Carnemolla, B. (2018). Anti-cancer Therapies Employing IL-2 Cytokine Tumor Targeting: Contribution of Innate, Adaptive and Immunosuppressive Cells in the Anti-tumor Efficacy. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02905"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1038\/modpathol.2015.93","article-title":"Recombinant interferon-\u03b1 in myelofibrosis reduces bone marrow fibrosis, improves its morphology and is associated with clinical response","volume":"28","author":"Pizzi","year":"2015","journal-title":"Mod. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Tang, J., and Yang, R. (2025). All-Trans Retinoic Acid Induces Differentiation and Downregulates Stemness Markers and MGMT Expression in Glioblastoma Stem Cells. Cells, 14.","DOI":"10.20944\/preprints202504.1196.v1"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/j.stem.2024.06.003","article-title":"Cancer stem cell mimicry for immune evasion and therapeutic resistance","volume":"31","author":"Saw","year":"2024","journal-title":"Cell Stem Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s00262-016-1916-4","article-title":"Low-dose interleukin-2 impairs host anti-tumor immunity and inhibits therapeutic responses in a mouse model of melanoma","volume":"66","author":"Zloza","year":"2017","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1136\/annrheumdis-2018-214229","article-title":"Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial","volume":"78","author":"Rosenzwajg","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"104539","DOI":"10.1016\/j.ebiom.2023.104539","article-title":"A systematic review of interleukin-2-based immunotherapies in clinical trials for cancer and autoimmune diseases","volume":"90","author":"Raeber","year":"2023","journal-title":"eBioMedicine"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1182\/blood-2008-12-164004","article-title":"The granulocyte-macrophage colony-stimulating factor receptor: Linking its structure to cell signaling and its role in disease","volume":"114","author":"Hercus","year":"2009","journal-title":"Blood"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4815","DOI":"10.4049\/jimmunol.159.10.4815","article-title":"Pivotal role of endogenous TNF-alpha in the induction of functional inactivation and apoptosis in NK cells","volume":"159","author":"Jewett","year":"1997","journal-title":"J. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/BF01489488","article-title":"Interferon-alpha activates cytotoxic function but inhibits interleukin-2-mediated proliferation and tumor necrosis factor-alpha secretion by immature human natural killer cells","volume":"15","author":"Jewett","year":"1995","journal-title":"J. Clin. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"907","DOI":"10.4049\/jimmunol.156.3.907","article-title":"Target-induced inactivation and cell death by apoptosis in a subset of human NK cells","volume":"156","author":"Jewett","year":"1996","journal-title":"J. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/S0198-8859(03)00039-9","article-title":"Cytokine dependent inverse regulation of CD54 (ICAM1) and major histocompatibility complex class I antigens by nuclear factor kappaB in HEp2 tumor cell line: Effect on the function of natural killer cells","volume":"64","author":"Jewett","year":"2003","journal-title":"Hum. Immunol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2814\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T09:47:04Z","timestamp":1774000024000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2814"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,20]]},"references-count":52,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27062814"],"URL":"https:\/\/doi.org\/10.3390\/ijms27062814","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,20]]}}}