Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution
| Autor: | Guorong Xu, Kathleen M. Fisch, Isabella Jamieson Morris, Catriona Jamieson, Raymond Diep, Chanond A Nasamran, Ruben A. Mesa, Frida Holm, Amanda Birmingham, Jessica Pham, Wenxue Ma, Jane Isquith, Cayla Mason, Eduardo Reynoso, Yudou He, Phoebe Mondala, Roman Sasik, Sara Brin Rosenthal, Adam Mark, Mary Donohoe, Ludmil B. Alexandrov, Gabriel Pineda, Isabelle Oliver, J. Craig Venter, Luisa Ladel, Sanja Coso, Thomas Whisenant, Qingfei Jiang, Shawn Ali, Leslie Crews |
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| Rok vydání: | 2021 |
| Předmět: |
Myeloid
0301 basic medicine Gene isoform Enter keywords here Medical Physiology Acute Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Rare Diseases 0302 clinical medicine Downregulation and upregulation Stem Cell Research - Nonembryonic - Human Genetics medicine 2.1 Biological and endogenous factors Humans Aetiology Progenitor cell STAT3 Myeloproliferative neoplasm Cancer Cell Proliferation Inflammation Leukemia biology Myeloid leukemia Hematology Stem Cell Research medicine.disease Leukemia Myeloid Acute Haematopoiesis 030104 developmental biology Neoplastic Stem Cells biology.protein Cancer research Stem Cell Research - Nonembryonic - Non-Human Biochemistry and Cell Biology sense organs Stem cell 030217 neurology & neurosurgery |
| Zdroj: | Cell Rep Cell reports, vol 34, iss 4 |
| ISSN: | 2211-1247 |
| Popis: | Inflammation-dependent base deaminases promote therapeutic resistance in many malignancies. However, their roles in human pre-leukemia stem cell (pre-LSC) evolution to acute myeloid leukemia stem cells (LSCs) had not been elucidated. Comparative whole-genome and whole-transcriptome sequencing analyses of FACS-purified pre-LSCs from myeloproliferative neoplasm (MPN) patients reveal APOBEC3C upregulation, an increased C-to-T mutational burden, and hematopoietic stem and progenitor cell (HSPC) proliferation during progression, which can be recapitulated by lentiviral APOBEC3C overexpression. In pre-LSCs, inflammatory splice isoform overexpression coincides with APOBEC3C upregulation and ADAR1p150-induced A-to-I RNA hyper-editing. Pre-LSC evolution to LSCs is marked by STAT3 editing, STAT3β isoform switching, elevated phospho-STAT3, and increased ADAR1p150 expression, which can be prevented by JAK2/STAT3 inhibition with ruxolitinib or fedratinib or lentiviral ADAR1 shRNA knockdown. Conversely, lentiviral ADAR1p150 expression enhances pre-LSC replating and STAT3 splice isoform switching. Thus, pre-LSC evolution to LSCs is fueled by primate-specific APOBEC3C-induced pre-LSC proliferation and ADAR1-mediated splicing deregulation. |
| Databáze: | OpenAIRE |
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