title: Restoration of MYC-repressed targets mediates the negative effects of GM-CSF on RUNX1-ETO leukemogenicity.
abstract: Granulocyte macrophage-colony-stimulating factor (GM-CSF) signaling regulates hematopoiesis and immune responses. CSF2RA, the gene encoding the α-subunit for GM-CSF, is significantly downregulated in t(8;21) (RUNX1-ETO or RE) leukemia patients, suggesting that it may serve as a tumor suppressor. We previously reported that GM-CSF signaling is inhibitory to RE leukemogenesis. Here we conducted gene expression profiling of primary RE hematopoietic stem/progenitor cells (HSPCs) treated with GM-CSF to elucidate the mechanisms mediating the negative effects of GM on RE leukemogenicity. We observed that GM treatment of RE HSPCs resulted in a unique gene expression profile that resembles primary human cells undergoing myelopoiesis, which was not observed in control HSPCs. Additionally, we discovered that GM-CSF signaling attenuates MYC-associated gene signatures in RE HSPCs. In agreement with this, a functional screen of a subset of GM-CSF-responsive genes demonstrated that a MYC inhibitor, MXI1 (Max interactor 1), reduced the leukemic potential of RE HSPCs and t(8;21) acute myeloid leukemia (AML) cells. Furthermore, MYC knockdown and treatment with the BET (bromodomain and extra terminal domain) inhibitor JQ1 reduced the leukemic potential of t(8;21) cell lines. Altogether, we discovered a novel molecular mechanism mediating the GM-CSF-induced reduction in leukemic potential of RE cells, and our findings support MYC inhibition as an effective strategy for reducing the leukemogenicity of t(8;21) AML.
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Weng
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: S
authors.identifier: 0000-0002-3914-5376
authors.initials: S
authors.lastname: Matsuura
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: C T
authors.initials: CT
authors.lastname: Mowery
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Stoner
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Lam
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Ran
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Davis
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: M-C
authors.initials: MC
authors.lastname: Lo
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.|Department of Pathology and Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: D-E
authors.initials: DE
authors.lastname: Zhang
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D020869:Gene Expression Profiling; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics; D051379:Mice; D038042:Myelopoiesis / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000009:adverse effects*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000502:physiology; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000502:physiology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C079440:MXI1 protein, human; C489427:MYC protein, human; C493728:RUNX1 protein, human; C082222:RUNX1T1 protein, human