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3 results on '"Vicki Zhai"'

1. Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma

Author

Janith A. Seneviratne, Daenikka Ravindrarajah, Daniel R. Carter, Vicki Zhai, Amit Lalwani, Sukriti Krishan, Anushree Balachandran, Ernest Ng, Ruby Pandher, Matthew Wong, Tracy L. Nero, Shudong Wang, Murray D. Norris, Michelle Haber, Tao Liu, Michael W. Parker, Belamy B. Cheung, and Glenn M. Marshall

Subjects
biomarkers, cancer biology, chromatin modifications and dynamics, epigenetics, molecular biology, neuroblastoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background The child cancer, neuroblastoma (NB), is characterised by a low incidence of mutations and strong oncogenic embryonal driver signals. Many new targeted epigenetic modifier drugs have failed in human trials as monotherapy. Methods We performed a high‐throughput, combination chromatin‐modifier drug screen against NB cells. We screened 13 drug candidates in 78 unique combinations. Results We found that the combination of two histone methyltransferase (HMT) inhibitors: GSK343, targeting EZH2, and SGC0946, targeting DOT1L, demonstrated the strongest synergy across 8 NB cell lines, with low normal fibroblast toxicity. High mRNA expression of both EZH2 and DOT1L in NB tumour samples correlated with the poorest patient survival. Combination HMT inhibitor treatment caused activation of ATF4‐mediated endoplasmic reticulum (ER) stress responses. In addition, glutathione and several amino acids were depleted by HMT inhibitor combination on mass spectrometry analysis. The combination of SGC0946 and GSK343 reduced tumour growth in comparison to single agents. Conclusion Our results support further investigation of HMT inhibitor combinations as a therapeutic approach in NB.

Published
2024
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2. Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia

Author

Quentin Van Thillo, Jolien De Bie, Janith A. Seneviratne, Sofie Demeyer, Sofia Omari, Anushree Balachandran, Vicki Zhai, Wai L. Tam, Bram Sweron, Ellen Geerdens, Olga Gielen, Sarah Provost, Heidi Segers, Nancy Boeckx, Glenn M. Marshall, Belamy B. Cheung, Kiyotaka Isobe, Itaru Kato, Junko Takita, Timothy G. Amos, Ira W. Deveson, Hannah McCalmont, Richard B. Lock, Ethan P. Oxley, Maximilian M. Garwood, Ross A. Dickins, Anne Uyttebroeck, Daniel R. Carter, Jan Cools, and Charles E. de Bock

Subjects
Science
Abstract

SPI1 fusion genes in T-cell acute lymphoblastic leukemia (T-ALL) are commonly found with co-occurring NRAS mutations. Here, the authors show that the combination of these oncogenes is necessary to drive T-ALL in a murine model and that the oncogenic activity of the SPI1 fusion is dependent on β-catenin.

Published
2021
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3. Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia

Author

Timothy G. Amos, Janith A. Seneviratne, Quentin Van Thillo, Hannah McCalmont, Wai L. Tam, Jan Cools, Ira W. Deveson, Jolien De Bie, Sofie Demeyer, Nancy Boeckx, Richard B. Lock, Vicki Zhai, Sarah Provost, Kiyotaka Isobe, Junko Takita, Anne Uyttebroeck, Heidi Segers, Olga Gielen, Daniel R. Carter, Ethan P. Oxley, Charles E. de Bock, Bram Sweron, Maximilian M. Garwood, Belamy B. Cheung, Glenn M. Marshall, Ross A. Dickins, Anushree Balachandran, Itaru Kato, Ellen Geerdens, and Sofia Omari

Subjects
0301 basic medicine, Neuroblastoma RAS viral oncogene homolog, Oncogene Proteins, Fusion, Carcinogenesis, T-Lymphocytes, General Physics and Astronomy, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease_cause, Proto-Oncogene Mas, GTP Phosphohydrolases, Fusion gene, Mice, 0302 clinical medicine, hemic and lymphatic diseases, T Cell Transcription Factor 1, Cancer genetics, beta Catenin, Bone Marrow Transplantation, Mutation, Gene knockdown, Multidisciplinary, Leukemia, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, Science, T cell, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Proto-Oncogene Proteins, medicine, Animals, Humans, Acute lymphocytic leukaemia, SPI1, Membrane Proteins, Oncogenes, General Chemistry, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, HEK293 Cells, 030104 developmental biology, Catenin, Trans-Activators, Cancer research, Transcriptome
Abstract

Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the β-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/β-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/β-catenin interaction., SPI1 fusion genes in T-cell acute lymphoblastic leukemia (T-ALL) are commonly found with co-occurring NRAS mutations. Here, the authors show that the combination of these oncogenes is necessary to drive T-ALL in a murine model and that the oncogenic activity of the SPI1 fusion is dependent on β-catenin.

Published
2021
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