Biology subjects

Neuberg, D. S.

Publications and source records attributed to Neuberg, D. S..

4 recordsLinked to original sources

bioRxiv2025

Dynamic BH3 profiling predicts clinical outcomes in acute myeloid leukemia

Predictive biomarkers can potentially meet the need for improved drug assignment in acute myeloid leukemia (AML). Fewer than half of AML patients have actionable mutations: consequently, targeted therapy achieves remission in only a fraction of those who have them. Dynamic BH3 Profiling (DBP), a functional assay, can measure changes in ex vivo drug-induced apoptotic priming in multiple cancers. To assess the feasibility and predictive capacity of DBP in AML, we prospectively tested DBP using a fixed-drug panel in myeloblasts from 92 patients. We generated a database combining genetic and functional annotation. Established AML clinical and genetic prognostic characteristics were associated with drug-induced apoptotic priming. We observed distinct interpatient sensitivities to single drugs or combinations with the BCL2-inhibitor venetoclax, and intrapatient apoptotic priming differences based on CD123-expression within distinct cell subpopulations. DBP further predicted the likelihood of remission to chemotherapy and targeted agents, supporting its use to identify optimal personalized therapy. Statement of significanceDynamic BH3 profiling provides patient-specific drug vulnerability data in real-time to inform prognosis and therapy selection. Key takeawaysO_LIDynamic BH3 profiling can be performed on bone marrow and leukemic blood from AML patients in 48 hours. C_LIO_LIKnown clinical prognostic factors associate with drug-induced apoptotic priming in AML. C_LIO_LIDrug-induced apoptotic priming identifies drug vulnerabilities in individual patients and predicts clinical response to chemotherapy and small molecule inhibitors. C_LI

cancer biology↗

bioRxiv2025

Multitargeted Reduction of Inflammation and Atherosclerosis in Tet2-deficient CHIP via XPO1 Inhibition and Atf3 restoration

TET2 is the second most frequently mutated gene in clonal hematopoiesis of indeterminate potential (CHIP), driving hematopoietic stem cell clonal expansion and increasing the risk of myeloid malignancies. Affected individuals often develop atherosclerotic cardiovascular disease, exacerbated by hyperinflammatory TET2-mutant macrophages. Here, we show that the XPO1 nuclear export inhibitor eltanexor significantly reduces atherosclerotic plaque formation in a mouse model of Tet2-mutant CHIP. In addition, we investigated the mechanisms and gene expression pathways that underlie the proinflammatory phenotype that characterizes Tet2-mutant CHIP. Single-cell CITE-seq identified increased expression of multiple proinflammatory mediators in Tet2-mutant macrophages and in non-hematopoietic cells of the aortic wall, which was reduced by eltanexor treatment. Atf3, which encodes a core transcriptional modulator of inflammation, occupies and regulates the largest enhancer in wild-type macrophages. Tet2 loss diminished ATF3 binding to the regulatory loci of inflammatory mediators, which was restored upon XPO1 inhibition. These results provide new insights into drivers of heightened inflammation in TET2-mutant CHIP and highlight a novel therapeutic strategy for intervention.

immunology↗

bioRxiv2024

Coordinated Immune Cell Networks in the Bone Marrow Microenvironment Define the Graft versus Leukemia Response with Adoptive Cellular Therapy

Understanding how intra-tumoral immune populations coordinate to generate anti-tumor responses following therapy can guide precise treatment prioritization. We performed systematic dissection of an established adoptive cellular therapy, donor lymphocyte infusion (DLI), by analyzing 348,905 single-cell transcriptomes from 74 longitudinal bone-marrow samples of 25 patients with relapsed myeloid leukemia; a subset was evaluated by protein-based spatial analysis. In acute myelogenous leukemia (AML) responders, diverse immune cell types within the bone-marrow microenvironment (BME) were predicted to interact with a clonally expanded population of ZNF683+GZMB+ CD8+ cytotoxic T lymphocytes (CTLs) which demonstrated in vitro specificity for autologous leukemia. This population, originating predominantly from the DLI product, expanded concurrently with NK and B cells. AML nonresponder BME revealed a paucity of crosstalk and elevated TIGIT expression in CD8+ CTLs. Our study highlights recipient BME differences as a key determinant of effective anti-leukemia response and opens new opportunities to modulate cell-based leukemia-directed therapy.

cancer biology↗

bioRxiv2023

Targetable leukemia dependency on noncanonical PI3Kγ signaling

Phosphoinositide 3-kinase gamma (PI3K{gamma}) is implicated as a target to repolarize tumor-associated macrophages and promote anti-tumor immune responses in solid cancers. However, cancer cell-intrinsic roles of PI3K{gamma} are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukemias, we define a selective dependency on the PI3K{gamma} complex in a high-risk subset that includes myeloid, lymphoid, and dendritic lineages. This dependency is characterized by innate inflammatory signaling and activation of phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5), which encodes a regulatory subunit of PI3K{gamma} and stabilizes the active enzymatic complex. Mechanistically, we identify p21 (RAC1) activated kinase 1 (PAK1) as a noncanonical substrate of PI3K{gamma} that mediates this cell-intrinsic dependency independently of Akt kinase. PI3K{gamma} inhibition dephosphorylates PAK1, activates a transcriptional network of NF{kappa}B-related tumor suppressor genes, and impairs mitochondrial oxidative phosphorylation. We find that treatment with the selective PI3K{gamma} inhibitor eganelisib is effective in leukemias with activated PIK3R5, either at baseline or by exogenous inflammatory stimulation. Notably, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukemia xenografts with low baseline PIK3R5 expression, as residual leukemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Taken together, our study reveals a targetable dependency on PI3K{gamma}/PAK1 signaling that is amenable to near-term evaluation in patients with acute leukemia.

cancer biology↗