Biology subjects

Milne, P.

Publications and source records attributed to Milne, P..

3 recordsLinked to original sources

bioRxiv2026

Legionella and Mycobacterium populations exhibit geographic structuring across and within drinking water systems

Opportunistic pathogens (OPs) within the Legionella and Mycobacterium can persist and sometimes proliferate in drinking water systems and pose a risk to public health. Most prior research has focused on isolated system components of the drinking water treatment and distribution system and has rarely examined spatiotemporal dynamics across the entire source water, treatment process, and distribution system continuum. This study addresses this critical knowledge gap by quantitative profiling of microbial communities with full length 16S rRNA gene sequencing and flow cytometry, and associated water chemistry parameters, including disinfection byproducts (DBPs), across five full-scale utilities. These utilities reflect varying source water types, geographic locations, treatment regimes, and climate zones. Microbial communities, including Legionella and Mycobacterium populations, in distribution system were shaped by source water type and exhibited significant community divergence across utilities. Within the same genus, strain-level analyses revealed highly distinct Legionella and Mycobacterium sequence variants unique to each utility. Interestingly, a substantial proportion of Legionella and Mycobacterium amplicon sequence variants were both utility specific and often specific to locations within the distribution system, indicating strong geographic structuring both across and within drinking water systems. Understanding the mechanistic underpinnings of this geographic structuring is critical to develop robust strategies for managing and monitoring Legionella and Mycobacterium populations in drinking water systems.

microbiology↗

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↗

bioRxiv2019

Serum Flt3 ligand is a biomarker of progenitor cell mass and prognosis in acute myeloid leukemia

Fms-like tyrosine kinase 3 (Flt3) is a hematopoietic growth factor receptor expressed on lymphomyeloid progenitors and frequently, by AML blasts. Its ligand, Flt3L, has non-hematopoietic and lymphoid origins, is detectable during homeostasis and increases to high levels in states of hypoplasia due to genetic defects or treatment with cytoreductive agents. Measurement of Flt3L by ELISA reveals that Flt3+AML, is associated with depletion of Flt3L to undetectable levels. After induction chemotherapy, Flt3L is restored in patients entering CR, but remains depressed in those with refractory disease. Weekly sampling reveals marked differences in the kinetics of Flt3L response during the first 6 weeks of treatment, proportionate to the clearance of blasts and cellularity of the BM. In the UK NCRI AML17 trial, Flt3L was measured at day 26 in a subgroup of 135 patients with Flt3 mutation randomized to the tyrosine kinase inhibitor lestaurtinib. In these patients, attainment of CR was associated with higher Flt3L at day 26 (Mann-Whitney p < 0.0001). Day 26 Flt3L was also associated with survival: Flt3L [≤] 291pg/ml was associated with inferior event-free survival; and, Flt3L >1185pg/ml was associated with higher overall survival (p = 0.0119). Serial measurement of Flt3L in patients who had received a hematopoietic stem cell transplant for AML further illustrated the potential value of declining Flt3L to identify relapse. Together these observations suggest that measurement of Flt3L provides a non-invasive estimate of progenitor cell mass in most patients with AML, with the potential to inform clinical decisions.\n\nGraphical abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=151 HEIGHT=200 SRC=\"FIGDIR/small/588319_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (21K):\norg.highwire.dtl.DTLVardef@132f3f3org.highwire.dtl.DTLVardef@2e033eorg.highwire.dtl.DTLVardef@d70598org.highwire.dtl.DTLVardef@b0648a_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗