دورية
Mutant TET2Allele Dosage Affects Response to 5-Azacitidine in Acute Myeloid Leukemia
| العنوان: | Mutant TET2Allele Dosage Affects Response to 5-Azacitidine in Acute Myeloid Leukemia |
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| المؤلفون: | Stoelzel, Friedrich, Fordham, Sarah Elizabeth, Lin, Wei Yu, Blair, Helen, Ruhnke, Leo, Kunadt, Desireé, Mohr, Brigitte, Elstob, Claire, Allsop, Daniel, Nandana, Devi, Soura, Emmanouela-Niki, Park, Catherine, Fadly, Mohd, Rahman, Thahira, Heidenreich, Olaf, Altmann, Heidi, Jones, Gail, Menne, Tobias, Wobus, Manja, Jackson, Graham, Marr, Helen, Onel, Kenan, Meggendorfer, Manja, Haferlach, Torsten, Bornhäuser, Martin, Allan, James M. |
| المصدر: | Blood; November 2019, Vol. 134 Issue: 1, Number 1 Supplement 1 p113-113, 1p |
| مستخلص: | Personalised medicine is predicted to significantly improve outcomes for cancer patients, but implementation requires comprehensive genetic characterisation of malignant cells to identify therapeutically exploitable vulnerabilities. Using an isogenic cell model system with CRISPR-inactivated TET2in HEL acute myeloid leukemia (AML) cells and an orthotopic mouse xenograft model we demonstrate that mutant TET2allele dosage significantly affects sensitivity to 5-azacitidine hypomethylating therapy in AML, with biallelic mutation conferring hypersensitivity relative to monoallelic mutation. In the presence of 5-azacitidine, cell clones with biallelic TET2mutation had significantly lower cloning efficiency (P= 3 x 10-3) and proliferation in liquid culture (P< 1 x 10-4) compared to isogenic clones with monoallelic TET2mutation. Mixed populations of monoallelic and biallelicTET2mutated HEL AML cells were transplanted via intrafemoral injection into Rag2−/−Il2rg−/−129×Balb/c mice, and treatment with 5-azacitidine resulted in significant negative in vivoselection against TET2null cells relative to cells with monoallelic TET2mutation (P= 4 x 10-4). Methylation analysis revealed the acquisition of an overall hypermethylation phenotype in TET2null cells and RNA sequencing identified significant down-regulation of ABCB1transcript, resulting in concomitant pronounced down-regulation of the MDR1 drug efflux transporter at the protein level. RNA sequencing pathway analysis also identified a global effect on ribosome pathway (KEGG pathway ko03010) transcript levels (Padjusted= 0.002), evidenced by down-regulation of numerous RNA polymerase II components in cells with bi-allelic TET2mutation compared to cells with monoallelic TET2mutation. |
| قاعدة البيانات: | Supplemental Index |
| تدمد: | 00064971 15280020 |
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| DOI: | 10.1182/blood-2019-123047 |