Correction: LSD1 inhibition by tranylcypromine derivatives interferes with GFI1-mediated repression of PU.1 target genes and induces differentiation in AML.

The original version of this Article contained an error in the Acknowledgements section.

LSD1 inhibition by tranylcypromine derivatives interferes with GFI1-mediated repression of PU.1 target genes and induces differentiation in AML.

LSD1 has emerged as a promising epigenetic target in the treatment of acute myeloid leukemia (AML). We used two murine AML models based on retroviral overexpression of Hoxa9/Meis1 (H9M) or MN1 to study LSD1 loss of function in AML. The conditional knockout of Lsd1 resulted in differentiation with both granulocytic and monocytic features and increased ATRA sensitivity and extended the survival of mice with H9M-driven AML. The conditional knockout led to an increased expression of multiple genes regulated by the important myeloid transcription factors GFI1 and PU.1. These include the transcription factors GFI1B and IRF8. We also compared the effect of different irreversible and reversible inhibitors of LSD1 in AML and could show that only tranylcypromine derivatives were capable of inducing a differentiation response. We employed a conditional knock-in model of inactive, mutant LSD1 to study the effect of only interfering with LSD1 enzymatic activity. While this was sufficient to initiate differentiation, it did not result in a survival benefit in mice. Hence, we believe that targeting both enzymatic and scaffolding functions of LSD1 is required to efficiently treat AML. This finding as well as the identified biomarkers may be relevant for the treatment of AML patients with LSD1 inhibitors.

Adult Born Periglomerular Cells of Odorant Receptor Specific Glomeruli.

The OR37 subsystem is characterized by a variety of unique features. The odorant receptors (ORs) of this subfamily are selectively tuned to specific ligands which are supposed to play a role in social communication. OR37 expressing sensory neurons project their axons to a single receptor specific glomerulus per bulb which have been shown to be unusually stable in size and to possess a distinct repertoire of periglomerular cells. Since the neuronal network surrounding glomeruli is typically modified by the integration of adult born neurons, in this study it was investigated whether the number of adult born cells might be different for OR37 glomeruli compared to other OR-specific glomeruli. Towards this goal, 23 days after BrdU injection, BrdU labeled cells in the proximity of OR37A glomeruli as well as around OR18-2 and OR256-17 glomeruli were determined. It was found that the number of BrdU labeled cells in the periglomerular region of OR37A glomeruli was significantly lower compared to glomeruli of the other OR types. This finding was in line with a lower number of neuroblasts visualized by the marker protein doublecortin. Double labeling experiments for BrdU and marker proteins revealed that despite a relatively high number of calretinin expressing cells at the OR37A glomeruli, the number of cells co-stained with BrdU was quite low compared to other glomeruli, which may point to an individual turnover rate of this cell type for different glomeruli. Together, the results of the present study support the notion that the neuronal network at the OR37 glomeruli is less dynamic than that of other glomerulus types. This indicates a specific processing of social information in OR37 glomerular networks.

Structural Features of an OR37 Glomerulus: A Comparative Study.

In the olfactory bulb (OB) a sophisticated neuronal network mediates the primary processing of sensory information and extensive investigations over the past decades have greatly improved our understanding of the morphology and neuronal organization of the OB. However, efforts have mostly been focused on the different radial layers, typical for the OB and little attention has been paid to individual odorant receptor specific glomeruli, the first relay station of sensory information. It has been assumed that glomeruli processing odorant information out of different contextual fields might require accordingly specialized neuronal networks. In this study, we have analyzed and compared the structural features as well as cell types in the periglomerular (PG) region of three odorant receptor specific glomeruli. The investigations were focused on glomeruli of the receptor type OR37A, a member of the unique OR37 subsystem, in comparison to glomeruli of OR18-2, a class I odorant receptor and OR256-17, a class II receptor. Each of the odorant receptor types is known to be activated by distinct odorants and their glomeruli are located in different regions of the bulb. We found significant differences in the size of the glomeruli as well as in the variability of the glomerulus size in individual mice, whereby the OR37A glomeruli featured a remarkably stable size. The number of cells surrounding a given glomerulus correlated strongly with its size which allowed comparative analyses of the surrounding cell types for individual glomeruli. The proportion of PG cells labeled by NeuN as well as putative GABAergic neurons labeled by GAD65 was quite similar for the different glomerulus types. However, the number of cells expressing distinct calcium-binding proteins, namely parvalbumin (PV), calbindin (CB) or calretinin (CR) varied significantly among the three glomerulus types. These data suggest that each odorant receptor specific glomerulus type may be surrounded by a unique network of PG cells.

Decreased demand for olfactory periglomerular cells impacts on neural precursor cell viability in the rostral migratory stream.

The subventricular zone (SVZ) provides a constant supply of new neurons to the olfactory bulb (OB). Different studies have investigated the role of olfactory sensory input to neural precursor cell (NPC) turnover in the SVZ but it was not addressed if a reduced demand specifically for periglomerular neurons impacts on NPC-traits in the rostral migratory stream (RMS). We here report that membrane type-1 matrix metalloproteinase (MT1-MMP) deficient mice have reduced complexity of the nasal turbinates, decreased sensory innervation of the OB, reduced numbers of olfactory glomeruli and reduced OB-size without alterations in SVZ neurogenesis. Large parts of the RMS were fully preserved in MT1-MMP-deficient mice, but we detected an increase in cell death-levels and a decrease in SVZ-derived neuroblasts in the distal RMS, as compared to controls. BrdU-tracking experiments showed that homing of NPCs specifically to the glomerular layer was reduced in MT1-MMP-deficient mice in contrast to controls while numbers of tracked cells remained equal in other OB-layers throughout all experimental groups. Altogether, our data show the demand for olfactory interneurons in the glomerular layer modulates cell turnover in the RMS, but has no impact on subventricular neurogenesis.

Activation of the mouse odorant receptor 37 subsystem coincides with a reduction of novel environment-induced activity within the paraventricular nucleus of the hypothalamus.

Within the main olfactory system of mammals, a unique subsystem exists that is comprised of sensory neurons expressing odorant receptors (ORs) of the OR37 subfamily. These receptors are exclusive for mammals and are highly conserved across species. The mouse OR37 receptor subtypes A, B and C were shown to be activated by the long-chain aliphatic aldehydes pentadecanal, hexadecanal and heptadecanal, respectively. The search for biological sources of these compounds showed that bodily secretions from conspecifics activated the OR37A, B and C glomerulus. At the same time, the activity of cells in a target region of projection neurons from OR37 glomeruli, the paraventricular nucleus of the hypothalamus (PVN), was reduced compared with controls (clean test box). A large number of the activated cells in the PVN of mice that were placed into a clean test box were corticotropin-releasing hormone cells, indicating an induction of the stress axis due to the novel environment. The much lower number of activated cells of mice in a box enriched with bodily secretions from conspecifics indicated a reduced stress response. As bodily secretions from conspecifics activated the OR37 system and simultaneously reduced stress-induced activation of the PVN, it was tested whether the ligands for OR37 receptors could induce this effect. Indeed, a similarly reduced activity in the PVN was found in mice kept in a clean test box and exposed to a mixture of the OR37 ligands delivered via an air stream. These data indicate that the OR37 system may play a role in mediating a phenomenon called social buffering.