title: The homeobox gene DLX4 regulates erythro-megakaryocytic differentiation by stimulating IL-1β and NF-κB signaling.
abstract: Megakaryocyte and erythroid development are tightly controlled by a repertoire of cytokines, but it is not clear how cytokine-activated signaling pathways are controlled during development of these two lineages. Here, we identify that expression of DLX4, a transcription factor encoded by a homeobox gene, increases during megakaryopoiesis but decreases during erythropoiesis. Enforced expression of DLX4 in CD34(+) stem and progenitor cells and in bipotent K562 cells induced lineage markers and morphologic features of megakaryocytes and repressed erythroid marker expression and hemoglobin levels. Converse results were obtained when DLX4 was knocked down. Gene Ontology and Gene Set Enrichment Analyses of genome-wide changes in gene expression revealed that DLX4 induces a megakaryocytic transcriptional program and inhibits an erythroid transcriptional program. DLX4 also induced gene signatures that are associated with nuclear factor κB (NF-κB) signaling. The ability of DLX4 to promote megakaryocyte development at the expense of erythroid generation was diminished by blocking NF-κB activity or by repressing IL1B, a transcriptional target of DLX4. Collectively, our findings indicate that DLX4 exerts opposing effects on the megakaryocytic and erythroid lineages in part by inducing IL-1β and NF-κB signaling.
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 108, Houston, TX 77030, USA.
authors.forename: Bon Q
authors.initials: BQ
authors.lastname: Trinh
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 108, Houston, TX 77030, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Barengo
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 950, Houston, TX 77030, USA.
authors.forename: Sang Bae
authors.initials: SB
authors.lastname: Kim
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 950, Houston, TX 77030, USA.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Division of Pediatrics, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 853, Houston, TX 77030, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Zweidler-McKay
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 108, Houston, TX 77030, USA hnaora@mdanderson.org.
authors.forename: Honami
authors.initials: H
authors.lastname: Naora
mesh_terms: D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics*; D020014:K562 Cells; D055015:Megakaryocyte-Erythroid Progenitor Cells / Q000166:cytology*; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C105304:DLX4 protein, human; D018398:Homeodomain Proteins; C508585:IL1B protein, human; D053583:Interleukin-1beta; D016328:NF-kappa B; D014157:Transcription Factors
keywords: Cytokine; Erythroid; Homeobox gene; Megakaryocyte; NF-κB