Biology subjects

Carroll, A. J.

Publications and source records attributed to Carroll, A. J..

4 recordsLinked to original sources

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

Genotype-immunophenotype relationships in NPM1-mutant AML clonal evolution uncovered by single cell multiomic analysis

Acute myeloid leukemia (AML) is a multi-clonal disease, existing as a milieu of clones with unique but related genotypes as initiating clones acquire subsequent mutations. However, bulk sequencing cannot fully capture AML clonal architecture or the clonal evolution that occurs as patients undergo therapy. To interrogate clonal evolution, we performed simultaneous single cell molecular profiling and immunophenotyping on 43 samples from 32 NPM1-mutant AML patients at different stages of disease. Here we show that diagnosis and relapsed AML samples display similar clonal architecture patterns, but signaling mutations can drive increased clonal diversity specifically at relapse. We uncovered unique genotype-immunophenotype relationships regardless of disease state, suggesting leukemic lineage trajectories can be hard-wired by the mutations present. Analysis of longitudinal samples from patients on therapy identified dynamic clonal, transcriptomic, and immunophenotypic changes. Our studies provide resolved understanding of leukemic clonal evolution and the relationships between genotype and cell state in leukemia biology.

cancer biology↗

bioRxiv2024

PTPN11 Mutation Clonal Hierarchy in Acute Myeloid Leukemia

Mutations in protein tyrosine phosphatase non-receptor type 11 (PTPN11) have been considered late acquired mutations in acute myeloid leukemia (AML) development. To interrogate the ontogeny of PTPN11 mutations, we utilized single-cell DNA sequencing and identified that PTPN11 mutations can occur as initiating events in some AML patients when accompanied by strong oncogenic drivers, commonly NPM1 mutations. The co-driver role of PTPN11 mutations was confirmed in a novel murine model that exhibits an AML phenotype with early expansion of a diverse set of variably differentiated myeloid cells that engrafted into immunodeficient and immunocompetent mice. This immune diversity was reconstituted from early precursor cells when engrafted into immunodeficient mice. Moreover, immune diversity was also observed in the blast component of patient samples with NPM1 and PTPN11 mutations, providing novel antigen targets for immune based approaches in this subset of AML that is resistant to multiple targeted therapies.

cancer biology↗

bioRxiv2023

Systems analysis of long-term heat stress responses in the C4 grass Setaria viridis

A substantial number of C4 plants are utilized as food and fodder crops and often display improved resource use efficiency compared to C3 counterparts. However, their response to future extreme climates such as heatwaves is less understood. Setaria viridis, an emerging C4 model grass closely related to important C4 crops, was grown under high temperature for two weeks (42{degrees}C as compared to 28{degrees}C). High temperature resulted in stunted growth, but surprisingly had little impact on leaf area based photosynthetic rates. Rates of dark respiration significantly increased and there were major alterations in carbon and nitrogen metabolism in the heat-stressed plants, including reduced starch levels, accumulation of soluble sugars and an increase in leaf nitrogen content. Measurements of major phytohormones revealed a dramatic increase in abscisic acid in the heat-stressed plants. Leaf transcriptomics, proteomics and metabolomics analyses were carried out and mapped onto metabolic pathways of photosynthesis, respiration, carbon/nitrogen metabolism and hormone synthesis and signaling. Overall, upregulation of a number of stress-signaling pathways was observed, consistent with multiple potent signals leading to reduced plant growth. A systems model of plant response is presented based on oxidative stress, hormone and sugar signaling pathways.

plant biology↗