Biology subjects

Harrison, C. J.

Publications and source records attributed to Harrison, C. J..

6 recordsLinked to original sources

bioRxiv2026

CD180 identifies chemoresistant stem-like blasts and reveals a KMT2A-driven vulnerability in acute myeloid leukaemia

Relapse and chemoresistance remain major challenges in paediatric acute myeloid leukaemia (PAML), particularly in KMT2A-rearranged (KMT2A-r) subtypes where conventional markers such as CD34 are often absent, complicating measurable residual disease (MRD) detection. Leukaemia stem/regenerating cells (LSC/LRC) drive disease initiation, progression, and relapse, sharing stemness and chemoresistance properties that make them critical therapeutic targets. Using high-dimensional spectral flow cytometry, we identified CD180, a Toll-like receptor-like surface protein, as highly expressed on blasts and stem-like populations in KMT2A-r AML, while near absent on normal haematopoietic stem cells (HSCs). PAML KMT2A-r exhibits an unconventional immunophenotype dominated by CD34-CD180 populations. Integrated single-cell transcriptomics and functional profiling revealed CD180high clusters enriched for quiescence, oxidative phosphorylation, and KMT2A/LSC stemness signatures. CD180 cells demonstrated robust leukaemia-initiating capacity in xenograft models and persisted through therapy, re-emerging at relapse with phenotypic plasticity. Epigenomic analysis showed CD180 is a direct transcriptional target of the KMT2A::MLLT3 fusion complex, regulated by intragenic enhancers and downregulated by menin and BET inhibitors. Longitudinal single-cell analysis confirmed persistence and clonal evolution of CD180 populations during treatment and relapse, underscoring their mechanistic role in chemoresistance and disease progression. In summary, CD180 marks dynamic, relapse-driving populations in KMT2A-r PAML, persists through therapy, and importantly is near absent on normal HSCs, offering a selective therapeutic window. These findings position CD180 as a clinically actionable biomarker for MRD detection and a compelling therapeutic target for eradicating chemoresistant, stem-like cells in paediatric AML. Main PointsO_LICD180 marks chemoresistant, relapse-driving stem-like blasts in KMT2A-r paediatric AML, overcoming CD34-based MRD limitations. C_LIO_LIAbsent on normal HSCs, CD180 is a KMT2A::MLLT3 target and actionable for MRD, relapse prediction, and CD180-directed therapies. C_LI NoveltyThis study introduces CD180 as a novel biomarker and therapeutic target in AML, particularly KMT2A-rearranged subtypes where conventional markers are often absent. Unlike MRD strategies focused on bulk blasts, CD180 marks chemoresistant, stem-like populations driving relapse, critical reservoirs poorly defined in paediatric AML. This work fills a major gap in prognostic assessment and therapy by enabling precise detection of relapse-driving cells and offering a selective therapeutic window.

cancer biology↗

bioRxiv2025

B-cell precursor acute lymphoblastic leukaemia with IGH::CEBP rearrangement: what have we learnt over the years?

B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is a haematologic malignancy marked by the rapid proliferation of immature B cells in the bone marrow. While BCP-ALL most commonly affects children aged 1-5 years, it remains the most prevalent subtype of ALL in adolescence and adulthood. Chromosomal translocations involving the immunoglobulin (IG) locus and partner genes are proven useful for risk stratification and guiding clinical trials for therapeutic decision. This includes translocations with CCAAT/enhancer-binding proteins (CEBP), which are particularly rare. This rarity has limited efforts to characterise their genetic and clinical profiles, making risk stratification for IGH::CEBP-rearranged BCP-ALL challenging. In this letter, we review the clinical and demographic characteristics of all reported IGH::CEBP cases prior to 2024 and introduce new cases, with preliminary analysis to encourage further investigation into this poorly understood subtype. This study delivers new insights into the molecular and cytogenetic landscape of IGH::CEBP rearrangements in BCP-ALL, and lays a foundation for further investigation into CEBP family roles in haematopoietic development and leukemogenesis, especially in the context of Down syndrome. Finally, it introduces the ongoing international collaborative effort to assemble the largest known IGH::CEBP cohort for comprehensive risk stratification and prognostic evaluation.

cancer biology↗

bioRxiv2024

Pelops: A dedicated caller for DUX4 rearrangements from whole-genome sequencing data

Rearrangements involving the DUX4 gene (DUX4-r) define a subtype of paediatric and adult acute lymphoblastic leukaemia (ALL) with a favourable outcome. Currently, there is no standard of care diagnostic method for their confident identification. Here, we present an open-source software tool designed to detect DUX4-r from short-read, whole-genome sequencing (WGS) data. Evaluation on a cohort of 210 paediatric ALL cases showed that our method detects all known, as well as previously unidentified, cases of IGH::DUX4 and rearrangements with other partner genes. These findings demonstrate the possibility of robustly detecting DUX4-r using WGS in the routine clinical setting.

bioinformatics↗

bioRxiv2022

Diverse branching forms regulated by a core auxin transport mechanism in plants

Diverse branching forms have evolved multiple times across the tree of life to facilitate resource acquisition and exchange with the environment. In land plants, sporophyte branching enabled the diversification of the dominant vascular plant clade and arose in their last shared common ancestor; the bryophyte sisters to vascular plants are unbranched. Mechanisms for sporophyte branching are well known in Arabidopsis, where branch initiation and plastic branch outgrowth require directional auxin transport by PIN proteins. However, no broadly applicable genetic mechanisms for branching in vascular plants are known. We have used a combination of surgical and pharmacological treatments and PIN expression analyses in the lycophyte Selaginella kraussiana to identify PIN-mediated auxin transport as the ancestral mechanism for branching within vascular plants. We show that shortrange auxin transport out of the shoot tips promotes branching, and that branch dominance is coordinated by long-range auxin transport throughout the shoot system. Moreover, the plastic outgrowth of a branch from a unique organ system innovated in lycophytes (the rhizophore) is regulated by long-range auxin transport and associated with a transitory drop in PIN expression. We conclude that an ancestral mechanism for branching was independently recruited into plastic branch outgrowth in lycophytes and seed plants. Considered in conjunction with data from other species, our results highlight a pivotal role for the co-option of PINs into the evolution of branching in diverse plant forms.

plant biology↗

bioRxiv2021

Epigenetic regulator genes direct lineage switching in MLL-AF4 leukaemia

The fusion gene MLL-AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. However, relapse can be associated with a switch from acute lymphoblastic to acute myeloid leukaemia. Here we show that these myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate in either early, multipotent progenitors or committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes indicating that the execution and maintenance of lymphoid lineage differentiation is impaired. We show that this subversion is recurrently associated with the dysregulation of repressive chromatin modifiers, notably the nucleosome remodelling and deacetylation complex, NuRD. In addition to mutations, we show differential expression or alternative splicing of NuRD members and other genes is able to reprogram the B lymphoid into a myeloid gene regulatory network. Lineage switching in MLL-AF4 leukaemia is therefore driven and maintained by defunct epigenetic regulation. Statement of SignificanceWe demonstrate diverse cellular origins of lineage switched relapse within MLL-AF4 pro-B acute leukaemia. Irrespective of the developmental origin of relapse, dysregulation of NuRD and/or other epigenetic machinery underpins fundamental lineage reprogramming with profound implications for the increasing use of epitope directed therapies in this high-risk leukaemia.

cancer biology↗

bioRxiv2021

PpRPK2 modulates auxin homeostasis and transport to specify stem cell identity and plant shape in the moss Physcomitrella

Plant shape is determined by the activity of stem cells in the growing tips, and evolutionary changes in shape are linked to changes in stem cell function. The CLAVATA pathway is a key regulator of stem cell function in the multicellular shoot tips of Arabidopsis, acting via the WUSCHEL transcription factor to modulate hormone homeostasis. Broad scale evolutionary comparisons have shown that CLAVATA is a conserved regulator of land plant stem cell function, but CLAVATA acts independently of WUSCHEL-like (WOX) proteins in bryophytes, raising questions about the evolution of stem cell function and the role of the CLAVATA pathway. Here we show that the moss (Physcomitrella) CLAVATA pathway affects stem cell activity and overall plant shape by modulating hormone homeostasis. CLAVATA pathway components are expressed in the tip cells of filamentous tissues, regulating cell identity, filament branching patterns and plant spread. The PpRPK2 receptor-like kinase plays the major role and is expressed more strongly than other receptor-encoding genes. Pprpk2 mutants have abnormal responses to cytokinin, and auxin transport inhibition and show reduced PIN auxin transporter expression. We propose a model whereby PpRPK2 modulates PIN activity to determine stem cell identity and overall plant form in Physcomitrella. Our data indicate that CLAVATA-mediated auxin homeostasis is a fundamental property of plant stem cell function likely exhibited by the last shared common ancestor of land plants.

plant biology↗