Human pluripotent stem cells identify molecular targets of trisomy 12 in chronic lymphocytic leukemia patients
| Autor: | Antonino Neri, Fortunato Morabito, Jennifer C. Reid, Luca Orlando, Giovanna Cutrona, Andrew Leber, Mickie Bhatia, Massimo Gentile, Charisa Henly, Cameron G. Hollands, Josée Hébert, Diana Golubeva, Luca Agnelli, Brian Leber, Allison L. Boyd, Manlio Ferrarini |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Adult Male Pluripotent Stem Cells Chronic lymphocytic leukemia medicine.medical_treatment Preleukemia Gene Dosage Trisomy General Biochemistry Genetics and Molecular Biology Targeted therapy Cell Line 03 medical and health sciences 0302 clinical medicine Mice Inbred NOD hemic and lymphatic diseases medicine Animals Humans Gene Regulatory Networks Induced pluripotent stem cell Aged Aged 80 and over Models Genetic business.industry Cancer Reproducibility of Results Middle Aged medicine.disease IRAK4 Leukemia Lymphocytic Chronic B-Cell Xenograft Model Antitumor Assays 3. Good health 030104 developmental biology Cancer research Disease Progression Monoclonal B-cell lymphocytosis Female business 030217 neurology & neurosurgery |
| Zdroj: | Cell reports. 34(11) |
| ISSN: | 2211-1247 |
| Popis: | Identifying precise targets of individual cancers remains challenging. Chronic lymphocytic leukemia (CLL) represents the most common adult hematologic malignancy, and trisomy 12 (tri12) represents a quarter of CLL patients. We report that tri12 human pluripotent stem cells (hPSCs) allow for the identification of gene networks and targets specific to tri12, which are controlled by comparative normal PSCs. Identified targets are upregulated in tri12 leukemic cells from a cohort of 159 patients with monoclonal B cell lymphocytosis and CLL. tri12 signaling patterns significantly influence progression-free survival. Actionable targets are identified using high-content drug testing and functionally validated in an additional 44 CLL patient samples. Using xenograft models, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor is potent and selective against human tri12 CLL versus healthy patient-derived xenografts. Our study uses hPSCs to uncover targets from genetic aberrations and apply them to cancer. These findings provide immediate translational potential as biomarkers and targets for therapeutic intervention. |
| Databáze: | OpenAIRE |
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