{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T10:25:19Z","timestamp":1784543119446,"version":"3.55.0"},"reference-count":76,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T00:00:00Z","timestamp":1734393600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005677","name":"Jos\u00e9 Carreras Leuk\u00e4mie-Stiftung","doi-asserted-by":"publisher","award":["DJCLS 02 SP\/2023"],"award-info":[{"award-number":["DJCLS 02 SP\/2023"]}],"id":[{"id":"10.13039\/501100005677","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Homeobox genes encode transcription factors which organize differentiation processes in all tissue types including the hematopoietic compartment. Recently, we have reported physiological expression of TALE-class homeobox gene <jats:italic>IRX1<\/jats:italic> in early myelopoiesis restricted to the megakaryocyte-erythroid-progenitor stage and in early B-cell development to the pro-B-cell stage. In contrast, sister homeobox genes <jats:italic>IRX2<\/jats:italic>, <jats:italic>IRX3<\/jats:italic> and <jats:italic>IRX5<\/jats:italic> are aberrantly activated in the corresponding malignancies acute myeloid leukemia (AML) and B-cell progenitor acute lymphoid leukemia. Here, we examined the role of IRX-related homeobox gene <jats:italic>MKX<\/jats:italic> (also termed <jats:italic>IRXL1<\/jats:italic> or <jats:italic>mohawk<\/jats:italic>) in normal and malignant hematopoiesis. Screening of public datasets revealed silent <jats:italic>MKX<\/jats:italic> in normal myelopoiesis and B-cell differentiation, and aberrant expression in subsets of AML and multiple myeloma (MM) cell lines and patients. To investigate its dysregulation and oncogenic function we used AML cell line OCI-AML3 as model which strongly expressed <jats:italic>MKX<\/jats:italic> at both RNA and protein levels. We found that IRX5, JUNB and NFkB activated <jats:italic>MKX<\/jats:italic> in this cell line, while downregulated GATA2 and STAT5 inhibited its expression. MKX downstream analysis was conducted by siRNA-mediated knockdown and RNA-sequencing in OCI-AML3, and by comparative expression profiling analysis of a public dataset from MM patients. Analysis of these data revealed activation of <jats:italic>CCL2<\/jats:italic> which in turn promoted proliferation. Furthermore, MKX upregulated <jats:italic>SESN3<\/jats:italic> and downregulated <jats:italic>BCL2L11<\/jats:italic>, which may together underlie decreased etoposide-induced apoptosis. Finally, myeloid differentiation genes <jats:italic>CEBPD<\/jats:italic> and <jats:italic>GATA2<\/jats:italic> were respectively up- and downregulated by MKX. Taken together, our study identified <jats:italic>MKX<\/jats:italic> as novel aberrantly expressed homeobox gene in AML and MM, highlighting the function of <jats:italic>IRX1<\/jats:italic> in normal myelopoiesis and B-cell development, and of IRX-related genes in corresponding malignancies. Our data merit further investigation of <jats:italic>MKX<\/jats:italic> and its deregulated target genes to serve as novel markers and\/or potential therapeutic targets in AML patient subsets.<\/jats:p>","DOI":"10.1371\/journal.pone.0315196","type":"journal-article","created":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T18:26:37Z","timestamp":1734459997000},"page":"e0315196","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["IRX-related homeobox gene MKX is a novel oncogene in acute myeloid leukemia"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4431-8988","authenticated-orcid":true,"given":"Stefan","family":"Nagel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9448-416X","authenticated-orcid":true,"given":"Claudia","family":"Pommerenke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,12,17]]},"reference":[{"issue":"7","key":"pone.0315196.ref001","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1038\/s41375-022-01613-1","article-title":"The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic\/Dendritic Neoplasms","volume":"36","author":"JD Khoury","year":"2022","journal-title":"Leukemia"},{"issue":"10","key":"pone.0315196.ref002","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1056\/NEJMoa2024534","article-title":"Genome Sequencing as an Alternative to Cytogenetic Analysis in Myeloid Cancers","volume":"384","author":"EJ Duncavage","year":"2021","journal-title":"N Engl J Med"},{"issue":"7","key":"pone.0315196.ref003","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1038\/s41375-022-01620-2","article-title":"The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms","volume":"36","author":"R Alaggio","year":"2022","journal-title":"Leukemia"},{"issue":"11","key":"pone.0315196.ref004","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1182\/blood.2022015851","article-title":"The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee","volume":"140","author":"E Campo","year":"2022","journal-title":"Blood"},{"key":"pone.0315196.ref005","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1146\/annurev-immunol-032712-100024","article-title":"Transcriptional control of early T and B cell developmental choices","volume":"32","author":"E.V. 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