Biology subjects

Andreeff, M.

Publications and source records attributed to Andreeff, M..

5 recordsLinked to original sources

bioRxiv2026

Niche-level immune evasion in TP53 mutant AML residual disease revealed by spatial proteomics

Measurable (or minimal) residual disease (MRD) predicts relapse in patients with acute myeloid leukemia (AML). However, the biological and spatial characteristics of the AML bone marrow (BM) microenvironment (BMME) in which MRD cells survive remain largely unexplored; in particular, little is known of the BMME in TP53 mutant (TP53mut) AML. Here, we applied sequential immunofluorescence to whole BM biopsy specimens obtained from patients with TP53 wild-type (TP53WT) AML and TP53mut AML at diagnosis and in morphological complete remission (CR) to generate a comprehensive spatial map of the hematopoietic and BMME components. We identified TP53mut leukemia cells based on high p53 expression and delineated their spatial organization relative to stromal and immune niches. Biopsy-based cell composition analysis revealed marked B-cell depletion and an increased abundance of regulatory T-cells (Tregs) in TP53mut BM at CR. Unlike TP53WT BM, TP53mut BM at CR exhibited persistent TP53mut erythroid and immature leukemia cell clusters, spatially segregated from T-cell clusters, in perisinusoidal niches, suggesting niche-level immune evasion. Spatial profiling further revealed that Tregs characterized by FOXP3 upregulation were enriched near TP53mut MRD cells, indicating a locally enhanced immunosuppressive activity. Single-cell RNA sequencing-based cell-cell communication analysis identified erythroid-T-cell interactions mediated by the GDF15-CD48 axis as a potential mechanism of T-cell suppression, suggesting that the erythroid differentiation of TP53mut AML cells enhances local immunosuppression. Collectively, our results show a spatially organized immunosuppressive BMME in TP53mut AML and highlight the potential of spatial proteomics to identify actionable MRD niches in leukemias. Key pointsO_LITP53 mutant erythroid and immature leukemia cells form spatial clusters segregated from T-cells in complete remission. C_LIO_LIAn erythroblast-centered immunosuppressive niche characterizes TP53 mutant leukemia cells. C_LI

cancer biology↗

bioRxiv2025

Macrophage-secreted Pyrimidine Metabolites Confer Chemotherapy Resistance in Acute Myeloid Leukemia (AML)

The tumor microenvironment (TME) programs cancer cells to influence therapeutic responses. Macrophages residing in TME switch from pro-phagocytic to tumor-promoting and immunosuppressive phenotypes as cancer develops. While these pro-tumor functions of macrophages are associated with poor outcomes, the underlying mechanisms by which bone-marrow (BM)-associated macrophages fuel myeloid malignancy and their precise contribution to relapse remain undissected. Here, we show expansion of monocyte/macrophage population in leukemia patients post-chemotherapy relapse, and spatial proximity of macrophages to leukemia blasts in the BM niche. This proximity proved functionally consequential--depletion of macrophages delayed leukemia relapse post cytarabine (AraC), a frontline chemotherapy, in patient-derived xenografts (PDX) and syngeneic leukemia models. Mechanistically, a pyrimidine metabolite, deoxycytidine (dC), secreted by BM macrophages, is taken up by leukemia cells to directly inhibit deoxycytidine kinase (DCK) to hamper AraC activation and subsequent resistance in a cell non-autonomous manner. Diagnosis AML patients exhibited significantly higher circulating dC levels than healthy donors, and dC levels further increased following chemotherapy. SAMHD1, which catalyzes deoxynucleoside triphosphates (dNTPs) into deoxynucleoside, was highly abundant in macrophages and mediated dC accumulation. Blockade of dC production in mouse and human macrophages via genetic and pharmacological inhibition of SAMHD1 or DHODH, a critical enzyme in pyrimidine synthesis, restored AraC sensitivity. Combination with DHODH inhibitors significantly delayed AraC relapse in human PDX and mouse syngeneic AML models. Collectively, we identify a metabolic immune-leukemia crosstalk in which SAMHD1high macrophages mediates chemoresistance by secreting pyrimidine metabolites and propose macrophage metabolic reprogramming as a tractable strategy to overcome TME-driven chemoresistance in myeloid leukemia.

cancer biology↗

bioRxiv2025

Targetable BIRC5 dependency in therapy-resistant TP53 mutated acute myeloid leukemia

TP53 mutations across multiple cancers, including acute myeloid leukemia (AML), are associated with poor outcomes irrespective of treatment modality. However, druggable vulnerabilities beyond canonical p53 targets remain largely unexplored. We identify BIRC5 (encodes survivin), an inhibitor of the apoptosis protein (IAP) family, as a novel vulnerability in TP53 mutant AML using an unbiased, comprehensive multiomics approach -- whole-genome CRISPR knockout screen, bulk and single-cell RNA-seq, proteomics, and high-throughput drug screen. Mechanistically, BIRC5 deletion in AML restored caspase-9 and -3/7 activity and downregulated other IAPs, implicating BIRC5 as the central post-mitochondrial regulator for blocking apoptosis. p53 stabilization suppressed BIRC5 selectively in TP53 wild-type AML, explaining BIRC5 upregulation in TP53 mutant lines and AML primary tumors (n > 700). Longitudinal single-cell RNAseq (n = 22 pairs) revealed expansion of BIRC5high stem and progenitor leukemia clones in TP53 mutant AML patients post-VenAza therapy. Survivin and IAP inhibitors emerged as top combination partners with VenAza in TP53 mutant AML cells and showed potent in vivo leukemic blast inhibition in cell line and patient-derived xenograft models along with primary tumors. Beyond AML, BIRC5 was upregulated broadly across 17 of 25 TP53 mutant cancers in the TCGA cohort, and combination with survivin inhibitors overcame chemotherapy resistance in TP53 deficient triple negative breast and colorectal cancers. These findings define BIRC5 as a critical, targetable dependency and unveil survivin/IAP inhibition as a promising therapeutic axis to overcome p53-related resistance across both hematologic and solid malignancies. Key PointsO_LIBIRC5 upregulation is a novel dependency in TP53 mutant AML that mediates therapy resistance by evasion of apoptosis. C_LIO_LICombination with Survivin/IAP inhibitors overcomes venetoclax/azacitidine resistance in TP53 mutant AML. C_LI

cancer biology↗

bioRxiv2025

Dual MYC and GSPT1 Protein Degrader for MYC-Driven Cancers

Direct targeting of the oncoprotein MYC has long been attempted in cancer therapy, with limited success. We here identify a novel co-regulatory feedback loop of MYC and G1 to S phase transition protein 1 (GSPT1), where MYC promotes transcription of GSPT1, and GSPT1 senses stop codon of MYC to promote its translation. We report on the first-in-class dual MYC/GSPT1 protein degrader, GT19630. GT19630 significantly induced integrated stress response, abrogated oxidative phosphorylation through inhibition of the TCA cycle and induced cell death. Protein degradation of MYC was critical for efficacy of GT19630. GT19630 induced profound anti-proliferative effects and apoptosis agnostic to TP53 in a broad range of cancer cells, and is highly active in vivo in multiple, therapy-resistant hematologic and solid tumor models. Dual MYC/GSPT1 degradation was well tolerated in humanized CrbnI391V mice. In conclusion, we propose a novel treatment approach by directly targeting the MYC-GSPT1 axis in MYC-driven cancers. Statement of significanceMYC has been considered an undruggable protein. We found a targetable, novel positive co-regulatory feedback of MYC and GSPT1, a key translation terminator. The dual MYC/GSPT1 degrader GT19630 is highly active in MYC-driven tumors, with moderate effects on humanized Crbn mice, providing opportunities to improve treatment outcome of MYC-driven cancers.

cancer biology↗

bioRxiv2020

Clonal Evolution of Acute Myeloid Leukemia Revealed by High-Throughput Single-Cell Genomics

One of the pervasive features of cancer is the diversity of mutations found in malignant cells within the same tumor; a phenomenon called clonal diversity or intratumor heterogeneity. Clonal diversity allows tumors to adapt to the selective pressure of treatment and likely contributes to the development of treatment resistance and cancer recurrence. Thus, the ability to precisely delineate the clonal substructure of a tumor, including the evolutionary history of its development and the co-occurrence of its mutations, is necessary to understand and overcome treatment resistance. However, DNA sequencing of bulk tumor samples cannot accurately resolve complex clonal architectures. Here, we performed high-throughput single-cell DNA sequencing to quantitatively assess the clonal architecture of acute myeloid leukemia (AML). We sequenced a total of 556,951 cells from 77 patients with AML for 19 genes known to be recurrently mutated in AML. The data revealed clonal relationship among AML driver mutations and identified mutations that often co-occurred (e.g., NPM1/FLT3-ITD, DNMT3A/NPM1, SRSF2/IDH2, and WT1/FLT3-ITD) and those that were mutually exclusive (e.g., NRAS/KRAS, FLT3-D835/ITD, and IDH1/IDH2) at single-cell resolution. Reconstruction of the tumor phylogeny uncovered history of tumor development that is characterized by linear and branching clonal evolution patterns with latter involving functional convergence of separately evolved clones. Analysis of longitudinal samples revealed remodeling of clonal architecture in response to therapeutic pressure that is driven by clonal selection. Furthermore, in this AML cohort, higher clonal diversity ([≥]4 subclones) was associated with significantly worse overall survival. These data portray clonal relationship, architecture, and evolution of AML driver genes with unprecedented resolution, and illuminate the role of clonal diversity in therapeutic resistance, relapse and clinical outcome in AML.

cancer biology↗