title: Induced myelomonocytic differentiation in leukemia cells is accompanied by noncanonical transcription factor expression.
abstract: Transcription factors that drive non-neoplastic myelomonocytic differentiation are well characterized but have not been systematically analyzed in the leukemic context. We investigated widely used, patient-derived myeloid leukemia cell lines with proclivity for differentiation into granulocytes by retinoic acid (RA) and/or monocytes by 1,25-dihyrdroxyvitamin D3 (D3). Using K562 (FAB M1), HL60 (FAB M2), RA-resistant HL60 sublines, NB4 (FAB M3), and U937 (FAB M5), we correlated nuclear transcription factor expression to immunophenotype, G1/G0 cell cycle arrest and functional inducible oxidative metabolism. We found that myelomonocytic transcription factors are aberrantly expressed in these cell lines. Monocytic-lineage factor EGR1 was not induced by D3 (the monocytic inducer) but instead by RA (the granulocytic inducer) in lineage bipotent myeloblastic HL60. In promyelocytic NB4 cells, EGR1 levels were increased by D3, while Gfi-1 expression (which promotes the granulocytic lineage) was upregulated during D3-induced monocytic differentiation in HL60, and by RA treatment in monocytic U937 cells. Furthermore, RARα and VDR expression were not strongly correlated to differentiation. In response to different differentiation inducers, U937 exhibited the most distinct transcription factor expression profile, while similarly mature NB4 and HL60 were better coupled. Overall, the differentiation induction agents RA and D3 elicited cell-specific responses across these common FAB M1-M5 cell lines.
authors.affiliation: School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, USA.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Jensen
authors.affiliation: Department of Biology, Cornell University, Ithaca, NY, USA.
authors.forename: Harmony B
authors.initials: HB
authors.lastname: Yourish
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA.
authors.forename: Rodica P
authors.initials: RP
authors.lastname: Bunaciu
authors.affiliation: School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Varner
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Yen
keywords: AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; AhR, aryl hydrocarbon receptor; C/EBPα, CCAAT-enhancer binding protein α; CD, cluster of differentiation [marker]; D3, 1,25-dihydroxyvitamin D3; Differentiation; EGR1, early growth response protein 1; FAB, French–American–British [myeloid leukemia classification]; Gfi-1, growth factor independent protein 1; IRF-1, interferon regulatory factor 1; Lineage selection; Myeloid leukemia; Oct4, octamer-binding transcription factor 4; PU.1, binds PU-box, also called Spi-1; RA, retinoic acid; RARα, retinoic acid receptor α; Retinoic acid; VDR, vitamin D receptor; Vitamin D3