Biology subjects

Itkin, T.

Publications and source records attributed to Itkin, T..

4 recordsLinked to original sources

bioRxiv2026

MYC drives endothelial transformation and dedifferentiation in angiosarcoma

MYC amplification is the most common genetic alteration in radiation-associated angiosarcoma and is also present in a subset of de novo primary angiosarcoma, yet its oncogenic role in this vascular malignancy remains unclear. Here, we report that inducible, endothelial-specific MYC overexpression alone was sufficient to drive angiosarcomagenesis in mice. The resulting pulmonary angiosarcoma tumors exhibited impaired endothelial differentiation, indicative of MYC-driven lineage plasticity. Notably, MYC inactivation in dedifferentiated allografts induced growth arrest and restored endothelial gene expression, demonstrating MYC-dependent reversible cellular plasticity. Integrative analyses of MYC ChIP-seq, ATAC-seq, and RNA-seq revealed that overexpressed MYC preferentially occupied highly accessible promoters and activated genes involved in cell growth. Consistent with the murine findings, MYC-amplified human angiosarcomas were enriched for MYC target and cell-cycle programs and depleted of endothelial lineage signatures. MYC overexpression in human endothelial and angiosarcoma cells recapitulated these transcriptional changes, enhanced proliferation, and impaired endothelial tube formation. Together, our results establish MYC as an oncoprotein that promotes endothelial lineage plasticity to drive angiosarcoma initiation and progression.

cancer biology↗

bioRxiv2023

SINGLE CELL RESOLUTION SPATIAL MAPPING OF HUMAN HEMATOPOIESIS REVEALS AGING-ASSOCIATED TOPOGRAPHIC REMODELING

The spatial anatomy of hematopoiesis in bone marrow has been extensively studied in mice and other preclinical models, but technical challenges have precluded a commensurate exploration in humans. Institutional pathology archives contain thousands of paraffinized bone marrow core biopsy tissue specimens, providing a rich resource for studying the intact human bone marrow topography in a variety of physiologic states. Thus, we developed an end-to-end pipeline involving multiparameter whole tissue staining, in situ imaging at single-cell resolution, and artificial intelligence (AI)-based digital image analysis, and then applied it to a cohort of disease-free samples to survey alterations in the hematopoietic topography associated with aging. Our data indicate heterogeneity in marrow adipose tissue (MAT) content within each age group, and an inverse correlation between MAT content and proportions of early myeloid and erythroid precursors, irrespective of age. We identify consistent endosteal and perivascular positioning of hematopoietic stem and progenitor cells (HSPCs) with medullary localization of more differentiated elements and, importantly, uncover new evidence of aging-associated changes in cellular and vascular morphologies, microarchitectural alterations suggestive of inflammaging, and diminution of a potentially active megakaryocytic niche. Overall, our findings suggest that there is topographic remodeling of human hematopoiesis associated with aging. More generally, we demonstrate the potential to deeply unravel the spatial biology of normal and pathologic human bone marrow states using intact archival tissue specimens.

systems biology↗

bioRxiv2023

Transcriptional Activation of Regenerative Hematopoiesis via Vascular Niche Sensing

Transition between activation and quiescence programs in hematopoietic stem and progenitor cells (HSC/HSPCs) is perceived to be governed intrinsically and by microenvironmental co-adaptation. However, HSC programs dictating both transition and adaptability, remain poorly defined. Single cell multiome analysis divulging differential transcriptional activity between distinct HSPC states, indicated for the exclusive absence of Fli-1 motif from quiescent HSCs. We reveal that Fli-1 activity is essential for HSCs during regenerative hematopoiesis. Fli-1 directs activation programs while manipulating cellular sensory and output machineries, enabling HSPCs co-adoptability with a stimulated vascular niche. During regenerative conditions, Fli-1 presets and enables propagation of niche-derived Notch1 signaling. Constitutively induced Notch1 signaling is sufficient to recuperate functional HSC impairments in the absence of Fli-1. Applying FLI-1 modified-mRNA transduction into lethargic adult human mobilized HSPCs, enables their vigorous niche-mediated expansion along with superior engraftment capacities. Thus, decryption of stem cell activation programs offers valuable insights for immune regenerative medicine.

cell biology↗

bioRxiv2021

Engineering a niche supporting haematopoietic stem cell development using integrated single cell transcriptomics

Haematopoietic stem cells (HSCs) develop from haemogenic endothelium (HE) within embryonic arterial vessels such as the aorta of the aorta-gonad-mesonephros region (AGM). To identify the signals responsible for HSC formation, we used single cell RNA-sequencing to simultaneously analyze the transcriptional profiles of AGM-derived cells transitioning from HE to HSC, and AGM-derived endothelial cells which provide signals sufficient to support HSC maturation and self-renewal. Pseudotemporal ordering revealed dynamics of gene expression during the HE to HSC transition, identifying surface receptors specifically expressed on developing HSCs. Transcriptional profiles of niche endothelial cells enabled identification of corresponding ligands, including those signaling to Notch receptors, VLA-4 integrin, and CXCR4, which, when integrated in an engineered platform, were sufficient to support the generation of engrafting HSCs. These studies provide a transcriptional map of the signaling interactions necessary for the development of HSCs and advance the goal of engineering HSC for therapeutic applications.

developmental biology↗