Biology subjects

Hadland, B. K.

Publications and source records attributed to Hadland, B. K..

3 recordsLinked to original sources

bioRxiv2025

Inhibition of farnesyltransferase activity diminishes hematopoietic stem cell ex vivo expansion ability

ABSTRACT/SUMMARYThe rationale underlying this work is that elucidating the contribution of farnesyltransferase activity to hematopoietic stem cell expansion ex vivo will provide knowledge needed to better support hematopoietic stem cell expansion techniques for clinical applications that rely on this approach, like hematopoietic cell transplants and gene therapy. We discovered that pharmacological inhibition of farnesyltransferase activity with lonafarnib substantially diminished the ex vivo expansion potential of human and mouse hematopoietic stem cells, highlighting that hematopoietic stem cells rely on isoprenoids for their ex vivo maintenance.

cell biology↗

bioRxiv2023

Chromatin Profiling of CBFA2T3-GLIS2 AMLs Identifies Key Transcription Factor Dependencies and BRG1 Inhibition as a Novel Therapeutic Strategy

Oncogenic fusions involving transcription factors are present in the majority of pediatric leukemias; however, the context-specific mechanisms they employ to drive cancer remain poorly understood. CBFA2T3-GLIS2 (C/G) fusions occur in treatment-refractory acute myeloid leukemias and are restricted to young children. To understand how the C/G fusion drives oncogenesis we applied CUT&RUN chromatin profiling to an umbilical cord blood/endothelial cell (EC) co-culture model of C/G AML that recapitulates the biology of this malignancy. We find C/G fusion binding is mediated by its zinc finger domains. Integration of fusion binding sites in C/G- transduced cells with Polycomb Repressive Complex 2 (PRC2) sites in control cord blood cells identifies MYCN, ZFPM1, ZBTB16 and LMO2 as direct C/G targets. Transcriptomic analysis of a large pediatric AML cohort shows that these genes are upregulated in C/G patient samples. Single cell RNA-sequencing of umbilical cord blood identifies a population of megakaryocyte precursors that already express many of these genes despite lacking the fusion. By integrating CUT&RUN data with CRISPR dependency screens we identify BRG1/SMARCA4 as a vulnerability in C/G AML. BRG1 profiling in C/G patient-derived cell lines shows that the CBFA2T3 locus is a binding site, and treatment with clinically-available BRG1 inhibitors reduces fusion levels and downstream C/G targets including N-MYC, resulting in C/G leukemia cell death and extending survival in a murine xenograft model.

cancer biology↗

bioRxiv2021

Multipotent progenitors and hematopoietic stem cells arise independently during the endothelial to hematopoietic transition in the early mouse embryo

During embryogenesis, waves of hematopoietic progenitors develop from hemogenic endothelium (HE) prior to the emergence of self-renewing hematopoietic stem cells (HSC). Although previous studies have shown that yolk sac-derived erythromyeloid progenitors and HSC emerge from distinct populations of HE, it remains unknown whether the earliest lymphoid-competent progenitors, multipotent progenitors, and HSC originate from common HE. Here we demonstrate by clonal assays and single cell transcriptomics that rare HE with functional HSC potential in the early murine embryo are distinct from more abundant HE with multilineage hematopoietic potential that fail to generate HSC. Specifically, HSC-competent HE are characterized by expression of CXCR4 surface marker and by higher expression of genes tied to arterial programs regulating HSC dormancy and self-renewal. Together, these findings suggest a revised model of developmental hematopoiesis in which the initial populations of multipotent progenitors and HSC arise independently from HE with distinct phenotypic and transcriptional properties.

developmental biology↗