Abstract
Abstract 1229
Eto-family proteins were first discovered as translocation fusion in AML1 (Runx1), a gene most frequently disrupted in human leukemia. Of the translocations that disrupt the AML1 gene in leukemia, Eto1(MTG8)/AML1 translocation accounts for ∼15% of Acute Myeloid Leukemia (AML). The Eto-family proteins function as transcriptional co-repressors that bind to DNA-binding transcription factors to regulate their target genes. Eto2 (MTG16) is an Eto-family member implicated in secondary or therapy-related AML, although recent reports provide evidence for Eto2/MTG16 translocations in de novo AML as well. Furthermore, recent studies have highlighted a role for MTG16 in HSC self renewal and T cell lineage specification, indicating its emerging role overall in hematopoiesis.
The co-repressor function of Eto for E-proteins has been described previously in the context of Eto/AML1 fusion proteins. E-proteins are a class of basic-helix-loop-helix (bHLH) transcription factors that play an important role in hematopoiesis. Among the E-protein family, the role of E2A has been extensively studied in B and T cell development. Recently, our lab discovered the specific requirement of the E-protein E2-2 in the development of Plasmacytoid Dendritic Cells (pDC). pDC are the professional interferon producing (IPC) cells of our immune system important in anti-viral, anti-tumor and auto-immunity. pDC are a subtype of the antigen-presenting classical Dendritic Cells (cDC) with distinct structural and functional properties. Recently, we demonstrated that the putative cell fate plasticity of pDC was a direct manifestation of continuous E2-2 function. Using pDC-reporter mice in which E2-2 could be inducibly deleted from mature pDC we showed that the continuous expression of E2-2 was required to prevent the conversion of pDC to cDC.
Here we report our current studies that investigate the molecular players underlying the E2-2 orchestrated genetic program for pDC cell fate decision and maintenance. Analyzing the transcriptome of the transitioning pDC, we have identified MTG16 as an important player in the fine regulation of DC lineage decisions. Using knock-out and chimeric mice, progenitor studies, promoter and biochemical analyses, we demonstrate MTG16 as an important E2-2 corepressor, promoting E2-2 mediated genetic program. We report that in order to facilitate the pDC cell fate, MTG16 enables E2-2 to suppress the cDC gene expression program, by negatively regulating the E-protein inhibitor Id2. The cell-fate conversion through deletion or overexpression of lineage-deciding transcriptional regulators has been described previously for B- and T cells. Theseh studies highlight the susceptibility of blood cells to aberrant functions of crucial transcriptional regulators, potentially leading to pathologic conditions. Therefore, understanding the interrelationship between the various genetic regulators that control lineage decisions and cell-fate plasticity is cardinal to accurate diagnosis and therapy for hematopoietic pathologies. Our study provides the first evidence for a physiological role of E-protein/Eto-protein interaction in dendritic cell lineage decision.
Disclosures:
No relevant conflicts of interest to declare.
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