Carlson, H. L. | Search bioRxiv

bioRxiv2026

The Canadian Pediatric Imaging Platform (C-PIP) Reference Sample: Neuroimaging Protocol and Cross-site Validation for Harmonized Multimodal Pediatric Imaging

Understanding how the human brain matures from infancy through adolescence is essential for identifying factors that influence health outcomes. Magnetic resonance imaging (MRI) provides powerful tools for characterizing structural, microstructural, functional, and metabolic aspects of brain development; however, many pediatric imaging studies are constrained by small sample sizes, limited geographic diversity, lack of longitudinal measurement, restricted age ranges, and heterogeneous acquisition protocols. While recent large-scale neuroimaging consortia have begun to address these challenges, such resources remain limited in the Canadian context, creating a critical gap. The Canadian Pediatric Imaging Platform (C-PIP) has developed a multisite neuroimaging framework across three of Canada's largest pediatric hospitals: Alberta Children's Hospital (Calgary), Centre Hospitalier Universitaire Sainte-Justine (Montreal), and the Hospital for Sick Children (Toronto). These three sites were united through a national initiative, leveraging high-performance MRI systems to accelerate Canadian neurodevelopmental research. In addition, C-PIP has implemented a centralized data sharing infrastructure to facilitate open science and collaborative research across institutions. Here, we describe the development and implementation of a multimodal MRI acquisition protocol designed to support multimodal longitudinal studies of typical and atypical brain development spanning infancy through adolescence. Within-site stability and cross-site stability of C-PIP core MRI sequences were evaluated using a travelling-participant study. The C-PIP MRI protocol establishes a harmonized, multisite imaging framework that supports large-scale investigations of pediatric brain development and disorders.

neuroscience↗

bioRxiv2026

Mutant ASXL1 Drives Transcriptional Activation and Repression in Human Hematopoiesis

Mutations in the epigenetic regulator ASXL1 are common in myeloid malignancies and portend a near-universally poor prognosis. While multiple mechanisms for mutant ASXL1-dependent oncogenesis have been proposed, none have been functionally validated in the context of the human hematopoietic stem cell, where these mutations almost certainly arise. Here, we extensively characterized a CRISPR-engineered human hematopoietic stem and progenitor cell model of ASXL1 mutations. In this context, mutant ASXL1 expression decreases differentiation, increases clonogenicity in serial replating experiments, and improves engraftment in immunodeficient mice. We also show that endogenous truncating mutations in ASXL1 drive protein stabilization and confirm that mutant ASXL1 is resistant to proteasomal degradation. At the transcriptional level, these phenotypes are driven by significant repression of the stress-response genes and by increased expression of bromodomain and extra-terminal family protein targets. Using protein-interaction screens, genomic and functional approaches, we link the positive transcriptional changes in ASXL1-mutant cells to BRD4-dependent RNA polymerase II pause release and identify a mechanism for transcriptional repression via a previously uncharacterized interaction with the transcription factor MECOM. Finally, we demonstrate that ASXL1-mutant AML exhibits increased MECOM activity consistent with our gene-editing models. Collectively, these studies highlight a highly reproducible model of mutant ASXL1 in the appropriate cell context. Further, they are the first to functionally describe the mutant ASXL1 interactome in the context of the human HSC, identifying new dependencies with therapeutic potential.

cancer biology↗