{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T19:01:06Z","timestamp":1785438066932,"version":"3.56.0"},"reference-count":36,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","award":["5\/13\/31\/2018\/NCD-III"],"award-info":[{"award-number":["5\/13\/31\/2018\/NCD-III"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"publisher"}]},{"award":["5\/13\/31\/2018\/NCD-III"],"award-info":[{"award-number":["5\/13\/31\/2018\/NCD-III"]}],"id":[{"id":"https:\/\/ror.org\/0492wrx28","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100023000","name":"Yenepoya (Deemed to be) University","doi-asserted-by":"crossref","award":["YU\/Seed grant\/132-2022"],"award-info":[{"award-number":["YU\/Seed grant\/132-2022"]}],"id":[{"id":"10.13039\/100023000","id-type":"DOI","asserted-by":"crossref"}]},{"award":["YU\/Seed grant\/132-2022"],"award-info":[{"award-number":["YU\/Seed grant\/132-2022"]}],"id":[{"id":"https:\/\/ror.org\/029zfa075","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Leukemia is a hematopoietic defect, involving complex molecular and cellular alterations, in which dysregulated signaling through hematopoietic receptors, including c-MPL (c-Myeloproliferative Leukemia), has been implicated. The function of c-MPL is mostly regulated by the crosstalk and stoichiometry of its different isoforms. Although expression of c-MPL in hematological disorders has been studied, the regulation of its isoforms and their balance, functional roles, and mechanisms of action in conditions such as acute and chronic leukemia and myeloproliferative neoplasms remain poorly understood. The association of c-MPL isoforms with leukemia cell proliferation and aggressiveness was examined by immunophenotyping, immunofluorescence, RT-PCR, Western blotting and clonogenic assay. This study demonstrates that an increase in the ratio of c-MPL-Full Length (FL)\/c-MPL-Truncated (TR), the conserved isoforms of c-MPL, influences tumorigenic markers such as Ki67, Caspase-3, and BCL-2, thereby promoting aggressiveness in leukemic cell lines. Furthermore, we have observed that with an increase in the c- MPL-FL\/c-MPL-TR ratio, STAT5 activation increases, promoting the proliferative state of leukemic cells, thereby revealing c-MPL isoforms as a therapeutic target for leukemia. In this work, we observed an increased c-MPL expression in leukemic cell lines, but cell proliferation is independent of total c-MPL expression. Our study demonstrates the regulatory role of c-MPL isoforms, particularly c-MPL-FL, in increasing cell proliferation in leukemia cell lines. This finding is a step towards developing c-MPL isoform as a therapeutic target for leukemic conditions such as acute and chronic leukemias and myeloproliferative neoplasms, but it needs further investigation for complete validation.<\/jats:p>","DOI":"10.3390\/cimb48070713","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T09:51:09Z","timestamp":1783936269000},"page":"713","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Imbalance of c-MPL Isoform Promotes Tumorigenesis by Activating STAT-5 in Leukemic Cell Lines"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-2767-7781","authenticated-orcid":false,"given":"Mohammad Amjad","family":"Hussain","sequence":"first","affiliation":[{"name":"Cell Biology and Molecular Genetics Division, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangaluru 575018, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0854-5438","authenticated-orcid":false,"given":"Mithila","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"Cell Biology and Molecular Genetics Division, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangaluru 575018, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1171-2002","authenticated-orcid":false,"given":"Reginald Samson","family":"Valder","sequence":"additional","affiliation":[{"name":"Cell Biology and Molecular Genetics Division, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangaluru 575018, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9355-1714","authenticated-orcid":false,"given":"Suparna","family":"Laha","sequence":"additional","affiliation":[{"name":"Cell Biology and Molecular Genetics Division, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangaluru 575018, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"ref_1","first-page":"e1139","article-title":"Metabolic underpinnings of leukemia pathology and treatment","volume":"2","author":"Nemkov","year":"2019","journal-title":"Cancer Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/j.1600-065X.2010.00963.x","article-title":"Lymphoid and myeloid lineage commitment in multipotent hematopoietic progenitors","volume":"238","author":"Kondo","year":"2010","journal-title":"Immunol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1002\/stem.2897","article-title":"c-MPL is a candidate surface marker and confers self-renewal, quiescence, chemotherapy resistance, and leukemia initiation potential in leukemia stem cells","volume":"36","author":"Li","year":"2018","journal-title":"Stem Cells"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5884","DOI":"10.1073\/pnas.1404354111","article-title":"Mpl expression on megakaryocytes and platelets is dispensable for thrombopoiesis but essential to prevent myeloproliferation","volume":"111","author":"Ng","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1080\/09537104.2021.1925102","article-title":"The thrombopoietin receptor: Revisiting the master regulator of platelet production","volume":"32","author":"Hitchcock","year":"2021","journal-title":"Platelets"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1007\/s13402-024-00988-w","article-title":"A review on the functional characteristics of the c-Myeloproliferative Leukemia (c-MPL) gene and its isoforms","volume":"47","author":"Hussain","year":"2024","journal-title":"Cell. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Pikman, Y., Lee, B.H., Mercher, T., McDowell, E., Ebert, B.L., Gozo, M., Cuker, A., Wernig, G., Moore, S., and Galinsky, I. (2006). MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med., 3.","DOI":"10.1371\/journal.pmed.0030270"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4198","DOI":"10.1182\/blood-2003-10-3471","article-title":"Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin","volume":"103","author":"Ding","year":"2004","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.critrevonc.2010.03.001","article-title":"Thrombopoietic growth factors in the treatment of immune thrombocytopenic purpura","volume":"77","author":"Wang","year":"2011","journal-title":"Crit. Rev. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1136\/mp.52.3.146","article-title":"Molecular detection of c-MPL thrombopoietin receptor gene expression in chronic myeloproliferative disorders","volume":"52","author":"Duensing","year":"1999","journal-title":"Mol. Pathol."},{"key":"ref_11","first-page":"287","article-title":"Novel drivers and modifiers of MPL-dependent oncogenic transformation identified by deep mutational scanning","volume":"135","author":"Bridgford","year":"2020","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_12","first-page":"1052","article-title":"Expression of c-MPL in leukemic stem cells from acute myeloid patients","volume":"20","author":"Yu","year":"2012","journal-title":"Zhongguoshi Yan Xue Ye Xue Za Zhi"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0145-2126(98)00132-5","article-title":"Correlation between lower c-MPL protein expression and favorable cytogenetic groups in acute myeloid leukemia","volume":"23","author":"Albitar","year":"1999","journal-title":"Leuk. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/j.molonc.2013.05.001","article-title":"Activation of Rac1 GTPase promotes leukemia cell chemotherapy resistance, quiescence and niche interaction","volume":"7","author":"Wang","year":"2013","journal-title":"Mol. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e41","DOI":"10.1111\/ijlh.12792","article-title":"Chronic myeloid leukemia, BCR-ABL1-positive with CALR and MPL mutations","volume":"40","author":"Klairmont","year":"2018","journal-title":"Int. J. Lab. Hematol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1172\/JCI79196","article-title":"Heterogeneity of leukemia-initiating capacity of chronic myelogenous leukemia stem cells","volume":"126","author":"Zhang","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1038\/sj.leu.2401893","article-title":"Expression of thrombopoietin receptor and its functional role in human B-precursor leukemia cells with 11q23 translocation or Philadelphia chromosome","volume":"14","author":"Iijima","year":"2000","journal-title":"Leukemia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.bbrc.2009.03.127","article-title":"CD90 and CD110 correlate with cancer stem cell potentials in human T-acute lymphoblastic leukemia cells","volume":"383","author":"Yamazaki","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Katheeja, M.N., Das, S.P., Das, R., and Laha, S. (2023). BRCA1 interactors, RAD50 and BRIP1, as prognostic markers for triple-negative breast cancer severity. Front. Genet., 14.","DOI":"10.3389\/fgene.2023.1035052"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100874","DOI":"10.1016\/j.nmni.2021.100874","article-title":"TRIzol-Based RNA extraction for detection protocol for SARS-CoV-2 of the coronavirus Disease 2019","volume":"41","author":"Amirouche","year":"2021","journal-title":"New Microbes New Infect."},{"key":"ref_21","unstructured":"Hajd\u00fach, M., and Dr\u00e1bek, J. (2021). Laboratory Techniques in Cellular and Molecular Medicine, Palacky University Olomouc."},{"key":"ref_22","first-page":"51998","article-title":"The soft agar colony formation assay","volume":"27","author":"Borowicz","year":"2014","journal-title":"J. Vis. Exp. JoVE"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"15","DOI":"10.12659\/MSMBR.893327","article-title":"Dual AO\/EB staining to detect apoptosis in osteosarcoma cells compared with flow cytometry","volume":"21","author":"Liu","year":"2015","journal-title":"Med. Sci. Monit. Basic Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.stem.2007.10.020","article-title":"Thrombopoietin\/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche","volume":"1","author":"Yoshihara","year":"2007","journal-title":"Cell Stem Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"328","DOI":"10.37897\/RMJ.2024.4.2","article-title":"The expressions of myeloid differentiation and non-lineage specific differentiation antigens among FAB subtypes of acute myeloid leukemia in Iraqi patients","volume":"71","author":"Maktoof","year":"2024","journal-title":"Romanian Med. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.fob.2015.09.008","article-title":"Induced myelomonocytic differentiation in leukemia cells is accompanied by noncanonical transcription factor expression","volume":"5","author":"Jensen","year":"2015","journal-title":"FEBS Open Bio"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Skopek, R., Palusi\u0144ska, M., Kaczor-Keller, K., Pingwara, R., Papierniak-Wygl\u0105da\u0142a, A., Schenk, T., Lewicki, S., Zelent, A., and Szyma\u0144ski, \u0141. (2023). Choosing the right cell line for acute myeloid leukemia (AML) research. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065377"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"36397","DOI":"10.1074\/jbc.M401386200","article-title":"A truncated isoform of c-MPL with an essential C-terminal peptide targets the full-length receptor for degradation","volume":"279","author":"Coers","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1111\/ijlh.13742","article-title":"Circ_0009910 sponges miR-491-5p to promote acute myeloid leukemia progression through modulating B4GALT5 expression and PI3K\/AKT signaling pathway","volume":"44","author":"Wu","year":"2022","journal-title":"Int. J. Lab. Hematol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"327","DOI":"10.4103\/jcrt.jcrt_1084_21","article-title":"Kermanian propolis induces apoptosis through upregulation of Bax\/Bcl-2 ratio in acute myeloblastic leukemia cell line (NB4)","volume":"19","author":"Salavatipour","year":"2023","journal-title":"J. Cancer Res. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"666","DOI":"10.4149\/neo_2013_085","article-title":"Overexpression of Bcl-2 protein predicts chemoresistance in acute myeloid leukemia: Its correlation with FLT3","volume":"60","author":"Mehta","year":"2013","journal-title":"Neoplasma"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e27159","DOI":"10.4161\/jkst.27159","article-title":"STAT5 in hematopoietic stem cell biology and transplantation","volume":"2","author":"Wang","year":"2013","journal-title":"JAK-STAT"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.1172\/JCI26674","article-title":"The molecular mechanisms that control thrombopoiesis","volume":"115","author":"Kaushansky","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_34","first-page":"941","article-title":"Ott1 (Rbm15) regulates thrombopoietin response in hematopoietic stem cells through alternative splicing of c-MPL","volume":"125","author":"Xiao","year":"2015","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_35","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_36","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1002\/j.1460-2075.1993.tb05925.x","article-title":"Murine c-mpl: A member of the hematopoietic growth factor receptor superfamily that transduces a proliferative signal","volume":"12","author":"Skoda","year":"1993","journal-title":"EMBO J."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/7\/713\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T04:13:26Z","timestamp":1784088806000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/7\/713"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,13]]},"references-count":36,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cimb48070713"],"URL":"https:\/\/doi.org\/10.3390\/cimb48070713","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,13]]}}}