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Role of Misfolded N-CoR Mediated Transcriptional Deregulation of Flt3 in Acute Monocytic Leukemia (AML)-M5 Subtype
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Role of Misfolded N-CoR Mediated Transcriptional Deregulation of Flt3 in Acute Monocytic Leukemia (AML)-M5 Subtype
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Journal Article
Role of Misfolded N-CoR Mediated Transcriptional Deregulation of Flt3 in Acute Monocytic Leukemia (AML)-M5 Subtype
2012
Overview
The nuclear receptor co-repressor (N-CoR) is a key component of the generic multi-protein complex involved in transcriptional control. Flt3, a key regulator of hematopoietic cell growth, is frequently deregulated in AML (acute myeloid leukemia). Here, we report that loss of N-CoR-mediated transcriptional control of Flt3 due to misfolding, contributes to malignant growth in AML of the M5 subtype (AML-M5). An analysis of hematopoietic genes in AML cells led to the identification of Flt3 as a transcriptional target of N-CoR. Flt3 level was inversely related to N-CoR status in various leukemia cells. N-CoR was associated with the Flt3 promoter in-vivo, and a reporter driven by the Flt3 promoter was effectively repressed by N-CoR. Blocking N-CoR loss with Genistein; an inhibitor of N-CoR misfolding, significantly down-regulated Flt3 levels regardless of the Flt3 receptor mutational status and promoted the differentiation of AML-M5 cells. While stimulation of the Flt3 receptor with the Flt3 ligand triggered N-CoR loss, Flt3 antibody mediated blockade of Flt3 ligand-receptor binding led to N-CoR stabilization. Genetic ablation of N-CoR potentiated Flt3 ligand induced proliferation of BA/F3 cells. These findings suggest that N-CoR-induced repression of Flt3 might be crucial for limiting the contribution of the Flt3 signaling pathway on the growth potential of leukemic cells and its deregulation due to N-CoR loss in AML-M5, could contribute to malignant growth by conferring a proliferative advantage to the leukemic blasts. Therapeutic restoration of N-CoR function could thus be a useful approach in restricting the contribution of the Flt3 signaling pathway in AML-M5 pathogenesis.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
/ Analysis
/ Biology
/ Cancer
/ Cell Differentiation - genetics
/ Cell Differentiation - physiology
/ Chromatin Immunoprecipitation
/ fms-Like Tyrosine Kinase 3 - genetics
/ fms-Like Tyrosine Kinase 3 - metabolism
/ Genes
/ Humans
/ Kinases
/ Leukemia
/ Leukemia, Monocytic, Acute - genetics
/ Leukemia, Monocytic, Acute - metabolism
/ Ligands
/ Medicine
/ Mutation
/ Nuclear Receptor Co-Repressor 1 - genetics
/ Nuclear Receptor Co-Repressor 1 - metabolism
/ Physics
/ Proteins
/ Real-Time Polymerase Chain Reaction
/ Reverse Transcriptase Polymerase Chain Reaction
/ Science
