Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia
Year: 2021
Type: article
Abstract: Children of Hispanic/Latino ancestry have increased incidence of high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) with poor prognosis. This leukemia is characterized by a single-copy deletion of the IKZF1 (IKAROS) tumor suppressor and increased activation of the PI3K/AKT/mTOR pathway. This identifies mTOR as an attractive therapeutic target in HR B-ALL. Here, we report that IKAROS represses MTOR transcription and IKAROS' ability to repress MTOR in leukemia is impaired by oncogenic CK2 kinase. Treatment with the CK2 inhibitor, CX-4945, enhances IKAROS activity as a repressor of MTOR, resulting in reduced expression of MTOR in HR B-ALL. Thus, we designed a novel therapeutic approach that implements dual targeting of mTOR: direct inhibition of the mTOR protein (with rapamycin), in combination with IKAROS-mediated transcriptional repression of the MTOR gene (using the CK2 inhibitor, CX-4945). Combination treatment with rapamycin and CX-4945 shows synergistic therapeutic effects in vitro and in patient-derived xenografts from Hispanic/Latino children with HR B-ALL. These data suggest that such therapy has the potential to reduce the health disparity in HR B-ALL among Hispanic/Latino children. The dual targeting of oncogene transcription, combined with inhibition of the corresponding oncoprotein provides a paradigm for a novel precision medicine approach for treating hematological malignancies.
Source: Leukemia
Authors: Zheng Ge, Chunhua Song, Yali Ding, Bi-Hua Tan, Dhimant Desai, Arati Sharma, Raghavendra Gowda, Feng Yue, Suming Huang, Vladimir Spiegelman, Jonathon L. Payne, Mark E. Reeves, Soumya Iyer, Pavan Kumar Dhanyamraju, Yuka Imamura, Daniel Bogush, Yevgeniya Bamme, Yiping Yang, Mario Soliman, Shriya Kane, Elanora Dovat, Joseph Schramm, Tommy Hu, Mary McGrath, Zissis C. Chroneos, Kimberly J. Payne, Chandrika Gowda, Sinisa Dovat
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,480
Funders: U.S. Department of Health and Human Services, Alex's Lemonade Stand Foundation for Childhood Cancer, Rally Foundation, St. Baldrick's Foundation, Hyundai Motor Group, Children's Miracle Network Hospitals, Four Diamonds, National Natural Science Foundation of China, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences, Hyundai Hope On Wheels
Awards: G1341114193, Visualization, modeling and validation of chromatin interaction data, G1668952339, G170609301, G2054187885, Targeting CK2 oncogenic pathway to overcome drug resistance in high-risk leukemia, G2440222559, 急性淋巴细胞白血病中IKAROS通过组蛋白修饰机制调控WDR5及作为新治疗靶点的研究, Role of macrophage polarization in multi-organ fibrosis of chronic GVHD, G3033725441, G353509602, Epigenetic Regulation in High-Risk Leukemia, G3853461424, G4469160630, G4767613893, G5395023489, The Role of Long Noncoding RNA in Hematopoiesis, G6226838940, G6242492906, G6371166291, G7293660262, Targeting CRLF2 and Ikaros Alterations to Reduce Health Disparities in Childhood Leukemia, Regulation of TAL1/SCL in T-Cell Leukemia, G820664904, G849953117, G8948392820, Regulation of tumor-infiltrating T cells by macrophages, High throughput interrogation of non-coding variants and 3D genome organization
OpenAlex ID: W3126761166