Certain oncology compounds exhibit fundamental pharmacokinetic (PK) disparities between healthy and malignant conditions. Given the effects of tumor-associated inflammation on enzyme and transporter expression, we performed a meta-analysis of CYP- and transporter-sensitive substrate clinical PK to quantitatively compare enzyme and transporter abundances between healthy volunteers (HV) and cancer patients (CP). Hepatic and intestinal CYP1A2, CYP2C19, and CYP3A4 abundance were subsequently adjusted via Simcyp's sensitivity analysis tool. Of the 11 substrates we investigated, seven displayed marked exposure differences >1.25-fold between CP and HV. Although CP studies are limited, meta-analysis-based reduction in CYP1A2, CYP2C19, and CYP3A4 enzyme abundances in a virtual oncology population effectively captures CP-PK for caffeine, theophylline, midazolam, simvastatin, omeprazole, and a subset of oncology compounds. These changes allow extrapolation from HV to CP, enhancing predictive capability; therefore, conducting simulations in this CYP-modified oncology (MOD-CP) population provides a more relevant characterization of CP-PK.
Transcription by RNA polymerase II (RNAPII) is accompanied by a conserved pattern of histone modifications that plays important roles in regulating gene expression. The establishment of this pattern requires phosphorylation of both Rpb1 (the largest RNAPII subunit) and the elongation factor Spt5 on their respective C-terminal domains (CTDs). Here we interrogated the roles of individual Rpb1 and Spt5 CTD phospho-sites in directing co-transcriptional histone modifications in the fission yeast Schizosaccharomyces pombe. Steady-state levels of methylation at histone H3 lysines 4 (H3K4me) and 36 (H3K36me) were sensitive to multiple mutations of the Rpb1 CTD repeat motif (Y1S2P3T4S5P6S7). Ablation of the Spt5 CTD phospho-site Thr1 reduced H3K4me levels but had minimal effects on H3K36me. Nonetheless, Spt5 CTD mutations potentiated the effects of Rpb1 CTD mutations on H3K36me, suggesting overlapping functions. Phosphorylation of Rpb1 Ser2 by the Cdk12 orthologue Lsk1 positively regulated H3K36me but negatively regulated H3K4me. H3K36me and histone H2B monoubiquitylation required Rpb1 Ser5 but were maintained upon inactivation of Mcs6/Cdk7, the major kinase for Rpb1 Ser5 in vivo, implicating another Ser5 kinase in these regulatory pathways. Our results elaborate the CTD ‘code’ for co-transcriptional histone modifications.
Emerging clonal complexity has brought into question the way in which we perceive and, in turn, treat disorders of the hematopoietic system. Former models of cellintrinsic clonal dominance driven by acquisition of driver genes in a stereotypic sequence are often insufficient in explaining observations such as clonal hematopoiesis, and new paradigms are in order.Here, we review the evidence within the hematologic malignancy field and also borrow from perspectives rooted in evolutionary biology to reframe pathogenesis of hematologic disorders as dynamic processes involving complex interplays of genetic and nongenetic subclones and the tissue microenvironment in which they reside.Significance: Hematopoietic malignant and premalignant syndromes exhibit vast clonal diversity that is subject to selection imposed by the tissue microenvironment, as well as artificial selection by therapy. Tackling these disorders requires an appreciation of heterogeneity at both genetic and nongenetic levels, which can be borrowed from evolutionary biology principles. Models and drug development strategies that veer away from targeting solely dominant clones and, instead, embrace this complexity to outsmart it are required for long-term remission.
Cell surfaces display a wide array of molecules that confer identity. While flow cytometry and cluster of differentiation (CD) markers have revolutionized cell characterization and purification, functionally heterogeneous cellular subtypes remain unresolvable by the CD marker system alone. Using hematopoietic lineages as a paradigm, we leverage the extraordinary molecular diversity of heparan sulfate (HS) glycans to establish cellular “glycotypes” by utilizing a panel of anti-HS single-chain variable fragment antibodies (scFvs). Prospective sorting with anti-HS scFvs identifies functionally distinct glycotypes within heterogeneous pools of mouse and human hematopoietic progenitor cells and enables further stratification of immunophenotypically pure megakaryocyte–erythrocyte progenitors. This stratification correlates with expression of a heptad of HS-related genes that is reflective of the HS epitope recognized by specific anti-HS scFvs. While we show that HS glycotyping provides an orthogonal set of tools for resolution of hematopoietic lineages, we anticipate broad utility of this approach in defining and isolating novel, viable cell types across diverse tissues and species.
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