Biology subjects

Leonard, E.

Publications and source records attributed to Leonard, E..

4 recordsLinked to original sources

bioRxiv2022

A Mesenchymal Cell Niche in Skin for Acute Myeloid Leukemia

Leukemia cutis or leukemic cell infiltration in skin is one of the common extramedullary manifestations of acute myeloid leukemia (AML) and signifies a poorer prognosis. However, its pathogenesis and maintenance remain understudied. Here, we report massive AML cell infiltration in the skin in a transplantation-induced MLL-AF9 AML mouse model. These AML cells could regenerate AML post-transplantation. Prospective niche characterization revealed that skin harbored mesenchymal progenitor cells (MPCs) with a similar phenotype as BM mesenchymal stem cells. These skin MPCs protected AML-initiating stem cells (LSCs) from chemotherapy in vitro partially via mitochondrial transfer. Furthermore, Lama4 deletion in skin MPCs promoted AML LSC proliferation and chemoresistance. Importantly, more chemoresistant AML LSCs appeared to be retained in Lama4-/- mouse skin post-cytarabine treatment. Our study reveals the characteristics and previously unrecognized roles of skin mesenchymal niches in maintaining and protecting AML LSCs during chemotherapy, meriting future exploration of their impact on AML relapse. A 40-word summary Sandhow et al have in transplantation-induced AML mouse models demonstrated the leukemia-regenerating capacity of AML cells infiltrated in the skin and the role of skin mesenchymal niches in maintaining/protecting AML cells, providing new insight into the pathology of leukemia cutis.

cancer biology↗

bioRxiv2022

Metabolite profiles across populations of Palmer amaranth (Amaranthus palmeri) highlight the specificity and inducibility of phytochemical response to glyphosate stress.

Modifications of the phytochemical profile form a vital component of physiological stress adaptation in plants. However, the specificity and uniqueness of phytochemical changes with respect to the identity of stressors is less known. Here, we investigated the commonality and specificity of metabolic perturbations induced by a specific stressor - glyphosate, and a general stressor - drought, across multiple glyphosate-resistant (GR) and -susceptible (GS) biotypes of a dominant agricultural weed, Amaranthus palmeri. In the absence of stress, the native metabolite profile of GS- and GR-biotypes was similar, and amplification of the EPSPS gene in GR-biotypes did not translate to a higher abundance of downstream metabolites. Further, glyphosate treatment initially inhibited the shikimate pathway in both GS- and GR-biotypes, from which the GR-biotypes recovered, indicating inducibility in the functionalization of the EPSPS enzyme. The accumulation of phenylpropanoids produced downstream of the shikimate pathway, was higher in GR-biotypes than GS-biotypes, with a preferential accumulation of compounds with higher antioxidant potential. However, this increase was not observed in response to drought treatment, where the metabolic perturbations were pervasive but limited in magnitude compared to glyphosate stress. Overall, while native phytochemistry of A. palmeri was similar irrespective of the level of glyphosate susceptibility, the specific stressor, glyphosate, imparted metabolic perturbations that were localized but higher in magnitude, while the specificity of phytochemical response to the general stressor, drought, was minimal. Taken together, these results suggest that, at the metabolic level, the glyphosate resistance mechanism in A. palmeri is partly induced and specific to herbicide stress. SIGNIFICANCE STATEMENTUnderstanding changes in physiology, especially those related to secondary metabolites with adaptogenic functions, is imperative to decipher the basis of stress adaptation in plants. This study provides critical information on native and stress-induced phytochemical differences between multiple glyphosate-resistant and -susceptible weed biotypes, thus, shedding light on the metabolome-level orchestration of gene amplification-mediated glyphosate resistance mechanism in an economically devastating weed, Palmer amaranth (Amaranthus palmeri).

plant biology↗

bioRxiv2021

DNA motif analysis of shear stress responsive endothelial enhancers reveals differential association of KLF and ETV/ETS binding sites with gained and lost enhancers

Endothelial cells (EC) lining blood vessels are exposed to mechanical forces, such as shear stress exerted by the flowing blood. These forces control many aspects of EC biology, including vascular tone, cell migration and proliferation in addition to cell size and shape. Despite a good understanding of the genes and signaling pathways responding to shear stress, our insights into the transcriptional regulation of these responses is much more limited. In particular, we do not know the different sets of regulatory elements (enhancers) that might control increases or decreases in gene expression. Here, we set out to study changes in the chromatin landscape of human umbilical vein endothelial cells (HUVEC) exposed to laminar shear stress. To do so, we performed ChIP-Seq for H3K27 acetylation, indicative of active enhancer elements and ATAC-Seq to mark regions of open chromatin in addition to RNA-Seq on HUVEC exposed to 6 hours of laminar shear stress. Our results show a correlation of gained and lost enhancers with up- and downregulated genes, respectively. DNA motif analysis revealed an over-representation of KLF transcription factor (TF) binding sites in gained enhancers, while lost enhancers contained more ETV/ETS motifs. We validated a subset of flow responsive enhancers using luciferase-based reporter constructs and CRISPR-Cas9 mediated genome editing. Lastly, we characterized shear stress responsive genes in ECs of zebrafish embryos using RNA-Seq. Together, our results reveal the presence of shear stress responsive DNA regulatory elements and lay the groundwork for the future exploration of these elements and the TFs binding to them in controlling EC biology.

genomics↗

bioRxiv2020

Distinct Vegfa isoforms control endothelial cell proliferation through PI3 kinase signalling mediated regulation of cdkn1a/p21

The formation of appropriately patterned blood vessel networks requires endothelial cell migration and proliferation. Signaling through the Vascular Endothelial Growth Factor A (VEGFA) pathway is instrumental in coordinating these processes. mRNA splicing generates short (diffusible) and long (extracellular matrix bound) Vegfa isoforms. The differences between these isoforms in controlling cellular functions are not understood. In zebrafish, vegfaa generates short and long isoforms, while vegfab only generates long isoforms. We found that mutations in vegfaa affected endothelial cell migration and proliferation. Surprisingly, mutations in vegfab specifically reduced endothelial cell proliferation. Analysis of downstream signaling revealed no change in MAPK (ERK) activation, while inhibiting PI3 kinase signaling phenocopied vegfab mutants. The cell cycle inhibitor cdkn1a/p21 was upregulated in vegfab deficient embryos. Accordingly, reducing cdkn1a/p21 restored endothelial cell proliferation. Together, these results suggest that extracellular matrix bound Vegfa acts through PI3K signaling to specifically control endothelial cell proliferation during angiogenesis independently of MAPK (ERK) regulation.

developmental biology↗