title: Role of misfolded N-CoR mediated transcriptional deregulation of Flt3 in acute monocytic leukemia (AML)-M5 subtype.
abstract: 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.
authors.affiliation: Cancer Science Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Dawn Sijin
authors.initials: DS
authors.lastname: Nin
authors.forename: Wai Kay
authors.initials: WK
authors.lastname: Kok
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Takahashi
authors.forename: Wee Joo
authors.initials: WJ
authors.lastname: Chng
authors.forename: Matiullah
authors.initials: M
authors.lastname: Khan
mesh_terms: D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D006801:Humans; D007948:Leukemia, Monocytic, Acute / Q000235:genetics / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: C539127:NCOR1 protein, human; D056971:Nuclear Receptor Co-Repressor 1; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3