Abstract
Nuclear receptor co-repressor (N-CoR) is the key component of generic co-repressor complex essential for the transcriptional control of genes involved in cellular hemostasis. We have recently reported that N-CoR actively represses Flt3, a key factor of hematopoietic stem cells (HSC) self-renewal and growth, and that de-repression of Flt3 by the misfolded N-CoR plays an important role in the pathogenesis of promyelocytic and monocytic acute myeloid leukemia (AML). The leukemic cells derived from the promyelocytic and monocytic AML are distinctly characterized by the ectopic reactivation of stem cell phenotypes in relatively committed myeloid compartment. However, the molecular mechanism underlying this phenomenon is not known. Here, we report that N-CoR function is essential for the commitment of primitive hematopoietic cells to the cells of myeloid lineage and that loss of N-CoR function due to misfolding is linked to the ectopic reactivation of generic stem cell phenotypes in promyelocytic and monocytic AML. Analysis of N-CoR and Flt3 transcripts in mouse hematopoietic cells revealed a positive correlation between N-CoR level and the commitment of myeloid cells and an inverse correlation between N-CoR and Flt3 levels in primitive as well as committed myeloid cells. Enforced N-CoR expression in mouse HSCs inhibited their growth and self-renewal potentials and promoted maturation toward cells of myeloid lineage, suggesting a role of N-CoR in the commitment of cells of myeloid lineage. In contrast to AML cells with natively folded N-CoR, primary and secondary promyelocytic and monocytic AML cells harboring the misfolded N-CoR were highly positive for Flt3 and myeloid antigen-based HSC marker CD34. Genetic and therapeutic restoration of N-CoR conformation significantly down-regulated the CD34 levels in monocytic AML cells, suggesting an important role of N-CoR in the suppression of CD34-based HSC phenotypes. These findings collectively suggest that N-CoR is crucial for the commitment of primitive hematopoietic cells to cells of myeloid lineage and that misfolded N-CoR may contribute to transformation of committed myeloid cells through the ectopic reactivation of Flt3/CD34-based stem cell phenotypes in promyelocytic and monocytic AML. Moreover, these findings provide novel mechanistic insights into the formation of leukemic stem cells in subsets of AML and identify the misfolded N-CoR as a subtype-specific biomarker of AML.
Highlights
Balanced transcriptional control of self-renewal and lineagespecific genes by the coordinated actions of co-activator and co-repressor proteins and sequence-specific transcriptional factors plays an important role in the normal growth and maturation of hematopoietic cells
We report that transcriptional repression mediated by nuclear receptor corepressor (N-CoR) is essential for the suppression of growth and self-renewal potentials of HSCs and that loss of N-CoR function due to misfolding leads to ectopic reactivation of Flt3 and CD34-based hematopoietic stem cell phenotypes in promyelocytic and monocytic AML. These findings suggest that transcriptional repression mediated by N-CoR might be crucial for the suppression of self-renewal potentials of primitive hematopoietic cells during their commitment and maturation to cells of myeloid lineage, and abrogation of this repression due to the misfolding and premature loss of N-CoR may contribute to the formation of leukemic stem cells (LSCs) or leukemia-initiating cells (LICs) through the ectopic reactivation of CD34+/Flt3+-based stem cell phenotype in promyelocytic and monocytic AML
Recent advances in the field of hematopoietic stem cell research has greatly improved our understanding about the role of specific transcription factors in the regulation of HSCs’ growth and lineage specification as well as their involvement in specific AML subtypes, very little is known about how the function of transcriptional co-factors, especially those involved in transcriptional repression, is modulated to allow selective temporal or spatial expression or suppression of various stage or lineage-specific genes in normal hematopoiesis and in AML
Summary
Balanced transcriptional control of self-renewal and lineagespecific genes by the coordinated actions of co-activator and co-repressor proteins and sequence-specific transcriptional factors plays an important role in the normal growth and maturation of hematopoietic cells. We have demonstrated that Flt, the cytokine receptor essential for the self-renewal of primitive hematopoietic cells [10, 11], is actively repressed by N-CoR and that misfolding and premature loss of N-CoR protein leads to the de-repression of Flt in promyelocytic and monocytic AML-derived primary and secondary leukemic cells [8] These findings suggested that N-CoR-mediated transcriptional repression of stem cell genes like Flt might be crucial for the suppression of self-renewal potential of hematopoietic cells during their commitment and differentiation to cells of myeloid lineage and that de-repression of Flt due to N-CoR misfolding may contribute to formation of leukemia-initiating cells (LICs) or leukemic stem cells (LSCs) through the ectopic reactivation of self-renewal potentials in relatively matured cells. These findings suggest that transcriptional repression mediated by N-CoR might be crucial for the suppression of self-renewal potentials of primitive hematopoietic cells during their commitment and maturation to cells of myeloid lineage, and abrogation of this repression due to the misfolding and premature loss of N-CoR may contribute to the formation of LSC or LIC through the ectopic reactivation of CD34+/Flt3+-based stem cell phenotype in promyelocytic and monocytic AML
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
