| RRC ID |
58024
|
| 著者 |
Cazzola A, Schlegel C, Jansen I, Bochtler T, Jauch A, Krämer A.
|
| タイトル |
TP53 deficiency permits chromosome abnormalities and karyotype heterogeneity in acute myeloid leukemia.
|
| ジャーナル |
Leukemia
|
| Abstract |
Abnormal karyotypes are common in cancer cells and frequently observed in acute myeloid leukemia (AML), in which complex karyotype aberrations are associated with poor prognosis. How exactly abnormal karyotypes arise and are propagated in AML is unclear. TP53 mutations and deletions are frequent in complex karyotype AML, suggesting a role of TP53 alterations in the development of chromosome abnormalities. Here, we generated isogenic TP53-knockout versions of the euploid AML cell line EEB to investigate the impact of TP53 on karyotype stability. We show that chromosome abnormalities spontaneously arise in TP53-deficient cells. Numerical aneuploidy could, to some extent, be propagated in a TP53-proficient setting, indicating that it does not necessarily trigger TP53 activation. In contrast, tolerance to structural chromosome aberrations was almost entirely restricted to TP53-knockout clones, all of which were able to continue proliferation in the presence of damaged DNA. Mechanistically, as a source of chromosome aberrations, limited numerical but not structural chromosomal instability was tolerated by TP53-wildtype cells. In contrast, structural instability was found only in TP53-knockout cells. Together, in myeloid cells TP53 loss allows for the development of complex karyotype aberrations and karyotype heterogeneity by perpetuation of chromosome segregation errors.
|
| 巻・号 |
33(11)
|
| ページ |
2619-2627
|
| 公開日 |
2019-11-1
|
| DOI |
10.1038/s41375-019-0550-5
|
| PII |
10.1038/s41375-019-0550-5
|
| PMID |
31444400
|
| MeSH |
Aneuploidy
CRISPR-Cas Systems
Cell Line, Tumor
Cell Proliferation
Chromosome Aberrations*
DNA Damage
Gene Deletion
Humans
In Situ Hybridization, Fluorescence
Karyotyping
Leukemia, Myeloid, Acute / diagnosis
Leukemia, Myeloid, Acute / genetics*
Mutation
Prognosis
Tumor Suppressor Protein p53 / genetics*
|
| IF |
8.665
|
| 引用数 |
2
|
| リソース情報 |
| ヒト・動物細胞 |
EEB(RCB2345) |
