4 results on '"Zhu, En-Ze"'
Search Results
2. A single-cell atlas identifies pretreatment features of primary imatinib resistance in chronic myeloid leukemia.
- Author
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Krishnan V, Schmidt F, Nawaz Z, Venkatesh PN, Lee KL, Ren X, Chan ZE, Yu M, Makheja M, Rayan NA, Lim MGL, Cheung AMS, Bari S, Chng WJ, Than H, Ouyang J, Rackham O, Tan TZ, Hwang WYK, Chuah C, Prabhakar S, and Ong ST
- Subjects
- Humans, Imatinib Mesylate pharmacology, Imatinib Mesylate therapeutic use, Prospective Studies, Blast Crisis, Drug Resistance, Neoplasm genetics, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism
- Abstract
Primary resistance to tyrosine kinase inhibitors (TKIs) is a significant barrier to optimal outcomes in chronic myeloid leukemia (CML), but factors contributing to response heterogeneity remain unclear. Using single-cell RNA (scRNA) sequencing, we identified 8 statistically significant features in pretreatment bone marrow, which correlated with either sensitivity (major molecular response or MMR) or extreme resistance to imatinib (eventual blast crisis [BC] transformation). Employing machine-learning, we identified leukemic stem cell (LSC) and natural killer (NK) cell gene expression profiles predicting imatinib response with >80% accuracy, including no false positives for predicting BC. A canonical erythroid-specifying (TAL1/KLF1/GATA1) regulon was a hallmark of LSCs from patients with MMR and was associated with erythroid progenitor [ERP] expansion in vivo (P < .05), and a 2- to 10-fold (6.3-fold in group A vs 1.09-fold in group C) erythroid over myeloid bias in vitro. Notably, ERPs demonstrated exquisite TKI sensitivity compared with myeloid progenitors (P < .001). These LSC features were lost with progressive resistance, and MYC- and IRF1-driven inflammatory regulons were evident in patients who progressed to transformation. Patients with MMR also exhibited a 56-fold expansion (P < .01) of a normally rare subset of hyperfunctional adaptive-like NK cells, which diminished with progressive resistance, whereas patients destined for BC accumulated inhibitory NKG2A+ NK cells favoring NK cell tolerance. Finally, we developed antibody panels to validate our scRNA-seq findings. These panels may be useful for prospective studies of primary resistance, and in assessing the contribution of predetermined vs acquired factors in TKI response heterogeneity., (© 2023 by The American Society of Hematology.)
- Published
- 2023
- Full Text
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3. An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia.
- Author
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Ko TK, Javed A, Lee KL, Pathiraja TN, Liu X, Malik S, Soh SX, Heng XT, Takahashi N, Tan JHJ, Bhatia R, Khng AJ, Chng WJ, Sia YY, Fruman DA, Ng KP, Chan ZE, Xie KJ, Hoi Q, Chan CX, Teo ASM, Velazquez Camacho O, Meah WY, Khor CC, Ong CTJ, Soon WJW, Tan P, Ng PC, Chuah C, Hillmer AM, and Ong ST
- Subjects
- Cell Differentiation, Chromatin Immunoprecipitation, DNA Methylation, Datasets as Topic, Enhancer of Zeste Homolog 2 Protein physiology, Gene Dosage, Gene Ontology, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Mutation, Polycomb Repressive Complex 1 genetics, Polycomb Repressive Complex 2 genetics, Transcriptome, Exome Sequencing, Whole Genome Sequencing, Blast Crisis genetics, Gene Expression Regulation, Leukemic genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Polycomb Repressive Complex 1 physiology, Polycomb Repressive Complex 2 physiology
- Abstract
Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations that confer stemness features to progenitor populations and resistance to BCR-ABL1 tyrosine kinase inhibitors. Comprehensive models of BC transformation have proved elusive because of the rarity and genetic heterogeneity of BC, but are important for developing biomarkers predicting BC progression and effective therapies. To better understand BC, we performed an integrated multiomics analysis of 74 CP and BC samples using whole-genome and exome sequencing, transcriptome and methylome profiling, and chromatin immunoprecipitation followed by high-throughput sequencing. Employing pathway-based analysis, we found the BC genome was significantly enriched for mutations affecting components of the polycomb repressive complex (PRC) pathway. While transcriptomically, BC progenitors were enriched and depleted for PRC1- and PRC2-related gene sets respectively. By integrating our data sets, we determined that BC progenitors undergo PRC-driven epigenetic reprogramming toward a convergent transcriptomic state. Specifically, PRC2 directs BC DNA hypermethylation, which in turn silences key genes involved in myeloid differentiation and tumor suppressor function via so-called epigenetic switching, whereas PRC1 represses an overlapping and distinct set of genes, including novel BC tumor suppressors. On the basis of these observations, we developed an integrated model of BC that facilitated the identification of combinatorial therapies capable of reversing BC reprogramming (decitabine+PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP., (© 2020 by The American Society of Hematology.)
- Published
- 2020
- Full Text
- View/download PDF
4. The arginase inhibitor Nω-hydroxy-nor-arginine (nor-NOHA) induces apoptosis in leukemic cells specifically under hypoxic conditions but CRISPR/Cas9 excludes arginase 2 (ARG2) as the functional target.
- Author
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Ng KP, Manjeri A, Lee LM, Chan ZE, Tan CY, Tan QD, Majeed A, Lee KL, Chuah C, Suda T, and Ong ST
- Subjects
- Antineoplastic Agents therapeutic use, Arginase genetics, Arginase metabolism, Arginine pharmacology, Arginine therapeutic use, CRISPR-Cas Systems genetics, Cell Cycle drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Enzyme Assays, Feasibility Studies, Gene Knockout Techniques, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Primary Cell Culture, RNA, Small Interfering metabolism, Antineoplastic Agents pharmacology, Apoptosis drug effects, Arginase antagonists & inhibitors, Arginine analogs & derivatives, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy
- Abstract
Cancer cells, including in chronic myeloid leukemia (CML), depend on the hypoxic response to persist in hosts and evade therapy. Accordingly, there is significant interest in drugging cancer-specific hypoxic responses. However, a major challenge in leukemia is identifying differential and druggable hypoxic responses between leukemic and normal cells. Previously, we found that arginase 2 (ARG2), an enzyme of the urea cycle, is overexpressed in CML but not normal progenitors. ARG2 is a target of the hypoxia inducible factors (HIF1-α and HIF2-α), and is required for the generation of polyamines which are required for cell growth. We therefore explored if the clinically-tested arginase inhibitor Nω-hydroxy-nor-arginine (nor-NOHA) would be effective against leukemic cells under hypoxic conditions. Remarkably, nor-NOHA effectively induced apoptosis in ARG2-expressing cells under hypoxia but not normoxia. Co-treatment with nor-NOHA overcame hypoxia-mediated resistance towards BCR-ABL1 kinase inhibitors. While nor-NOHA itself is promising in targeting the leukemia hypoxic response, we unexpectedly found that its anti-leukemic activity was independent of ARG2 inhibition. Genetic ablation of ARG2 using CRISPR/Cas9 had no effect on the viability of leukemic cells and their sensitivity towards nor-NOHA. This discrepancy was further evidenced by the distinct effects of ARG2 knockouts and nor-NOHA on cellular respiration. In conclusion, we show that nor-NOHA has significant but off-target anti-leukemic activity among ARG2-expressing hypoxic cells. Since nor-NOHA has been employed in clinical trials, and is widely used in studies on endothelial dysfunction, immunosuppression and metabolism, the diverse biological effects of nor-NOHA must be cautiously evaluated before attributing its activity to ARG inhibition., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
- Full Text
- View/download PDF
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