Biology subjects

Walker, C. J.

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

3 recordsLinked to original sources

bioRxiv2025

Multiomic characterization, early detection, and therapeutic targeting of myeloid sarcoma

Myeloid sarcoma, an aggressive extramedullary subtype of acute myeloid leukemia (AML), occurs in [~]10% of patients, and has not yet been included in large-scale genomic studies. The critical biological changes that drive tumor evolution are unknown, its detection in asymptomatic patients remains a clinical challenge, and treatment options are limited as patients are often excluded from clinical trials, rendering it a neglected disease entity. Based on comprehensive multi-omic profiling, we demonstrate that myeloid sarcoma evolves from medullary AML with distinct sitespecific clonal evolution patterns. Additionally, we show that circulating tumor DNA sequencing can serve as a non-invasive method for molecular profiling of myeloid sarcoma, offering a novel avenue in molecular diagnostics. We characterize unique transcriptional profiles of myeloid sarcoma, reflecting immune evasion and adaptation to an extramedullary microenvironment. We provide evidence for a key role of RAS pathway activation and demonstrate in murine models of myeloid sarcoma that RAS inhibition effectively reduces tumor burden. Overall, our data highlight key differences between medullary AML and myeloid sarcoma including universal molecular evolution and RAS pathway activation as hallmarks of the disease and nominate RAS inhibition as a promising therapeutic strategy for patients with myeloid sarcoma.

cancer biology↗

bioRxiv2025

Prognostic and Therapeutic Implications of BRAF Mutations in Acute Myeloid Leukemia

Mutations in the RAS/MAPK signaling pathway are recurrent in acute myeloid leukemia (AML), primarily involving NRAS and KRAS. In contrast, mutations in the gene encoding an effector protein, BRAF, occur at relatively lower frequencies in AML and are associated with poor outcomes. To date, no comprehensive analysis has assessed the clinical and molecular characteristics of BRAF-mutated AML. In this study, we report the identification of canonical and non-canonical BRAF mutations in [~]1% of 5,779 consecutive clinically and molecularly fully-annotated AML patients treated at two major United States Cancer Centers (50/5779 AML patients: 21 newly diagnosed AML; 9 relapsed/refractory; 20 newly diagnosed secondary AML). We performed single-cell multiomic analysis on a subset of AML samples. BRAF mutations were enriched in myelodysplasia-related AML (AML-MR), and most mutations were located outside the V600 hotspot. Single-cell multiomic profiling delineated BRAF mutation class-specific patterns of co-mutations, clonality, and immunophenotypes. Notably, BRAF mutations and other signaling co-mutation(s) could be found in the same cell, a finding that significantly diverges from prior studies of RAS-mutant AML. In this cohort, BRAF-mutant AML patients had poor overall survival with currently available treatments, including venetoclax-based regimens. Drug sensitivity data suggest possible avenues for targeted treatment of BRAF-mutated AML. Statement of SignificanceCanonical and non-canonical BRAF mutations are enriched in AML-MR and associate with poor survival outcomes. Single-cell multiomic profiling revealed unique co-mutation patterns and immunophenotypes that highlight RAS pathway addiction and nominate BRAF-mutated disease as a distinct subtype within RAS pathway-aberrated leukemias. Drug sensitivity screens suggest broad CDK or HSP90 inhibition in addition to BRAF/RAS-directed inhibition may be effective targeted therapies in this prognostically poor AML subtype.

cancer biology↗

bioRxiv2024

Humidity determines penetrance of a latitudinal gradient in genetic selection on the microbiota by Drosophila melanogaster

The fruit fly Drosophila melanogaster is a model for understanding how hosts and their microbial partners interact as the host adapts to wild environments. These interactions are readily interrogated because of the low taxonomic and numeric complexity of the flies bacterial communities. Previous work has established that host genotype, the environment, diet, and interspecies microbial interactions can all influence host fitness and microbiota composition, but the specific processes and characters mediating these processes are incompletely understood. Here, we compared the variation in microbiota composition between wild-derived fly populations when flies could choose between the microorganisms in their diets and when flies were reared under environmental perturbation (different humidities). We also compared the colonization of the resident and transient microorganisms. We show that the ability to choose between microorganisms in the diet and the environmental condition of the flies can influence the relative abundance of the microbiota. There were also key differences in the abundances of the resident and transient microbiota. However, the microbiota only differed between populations when the flies were reared at humidities at or above 50% relative humidity. We also show that elevated humidity determined the penetrance of a gradient in host genetic selection on the microbiota that is associated with the latitude the flies were collected from. Finally, we show that the treatment-dependent variation in microbiota composition is associated with variation in host stress survival. Together, these findings emphasize that host genetic selection on the microbiota composition of a model animal host can be patterned with the source geography, and that such variation has the potential to influence their survival in the wild. ImportanceThe fruit fly Drosophila melanogaster is a model for understanding how hosts and their microbial partners interact as hosts adapt in wild environments. Our understanding of what causes geographic variation in the fruit fly microbiota remains incomplete. Previous work has shown that the D. melanogaster microbiota has relatively low numerical and taxonomic complexity. Variation in the fly microbiota composition can be attributed to environmental characters and host genetic variation, and variation in microbiota composition can be patterned with the source location of the flies. In this work we explored three possible causes of patterned variation in microbiota composition. We show that host feeding choices, the host niche colonized by the bacteria, and a single environmental character can all contribute to variation in microbiota composition. We also show that penetrance of latitudinally-patterned host genetic selection is only observed at elevated humidities. Together, these results identify several factors that influence microbiota composition in wild fly genotypes and emphasize the interplay between environmental and host genetic factors in determining the microbiota composition of these model hosts.

microbiology↗