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.
Highlights
Acute Monoblastic/Monocytic leukemia (AML-M5) is a class of Acute Myeloid Leukemia (AML) classified under the M5 subtype in the French-American-British (FAB) classification
Our laboratory later reported that abrogation of N-CoRmediated transcriptional repression due to a misfolded conformation dependent loss (MCDL) of nuclear receptor co-repressor (N-CoR) protein was associated with the differentiation arrest of leukemic cells in Acute Promyelocytic Leukemia (APL) [13,14,15]
Our laboratory reported the role of N-CoR loss in the pathogenesis of APL and restoration of N-CoR function via Genistein, a tyrosine kinase inhibitor isolated from soy relieves the block in differentiation and induced cell death [14,15]
Summary
Acute Monoblastic/Monocytic leukemia (AML-M5) is a class of Acute Myeloid Leukemia (AML) classified under the M5 subtype in the French-American-British (FAB) classification. Despite the varied genetic background of the disease, the phenotypic presentation is almost identical, characterized by the differentiation arrest at the monoblast and/or promonocytic stage coupled with increased survival and proliferation capacities: a hallmark of AMLs. it is thought that aberrations involving key transcription factors and its associated co-activators and corepressors essential for the differentiation process are major driving forces of AML-M5 pathogenesis. It is thought that aberrations involving key transcription factors and its associated co-activators and corepressors essential for the differentiation process are major driving forces of AML-M5 pathogenesis One such factor is the nuclear receptor co-repressor (N-CoR), a key component of the multi-protein co-repressor complex involved in transcriptional repression mediated by various transcriptional factors. These findings coupled with reports indicating that NCoR knockout mice were embryonically lethal and appeared to die from anemia due to defects in definitive erythropoiesis [17], highlighted an essential role of N-CoR in the differentiation of cells during myeloid lineage commitment
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