Other
13 Authors
- Melo-Cardenas J,
- Xu Y,
- Gao B,
- Wei J,
- Tan C,
- Crispino JD,
- Kong S,
- Montauti E,
- Licht JD,
- Yu J,
- Fang D,
- Ji P,
- Kirsammer G
| First Author | Melo-Cardenas J | Year | 2018 |
| Journal | Blood | Volume | 132 |
| Issue | 4 | Pages | 423-434 |
| PubMed ID | 29844011 | Mgi Jnum | J:264756 |
| Mgi Id | MGI:6192991 | Doi | 10.1182/blood-2017-10-811760 |
| Citation | Melo-Cardenas J, et al. (2018) USP22 deficiency leads to myeloid leukemia upon oncogenic Kras activation through a PU.1-dependent mechanism. Blood 132(4):423-434 |
| abstractText | Ras mutations are commonly observed in juvenile myelomonocytic leukemia (JMML) and chronic myelomonocytic leukemia (CMML). JMML and CMML transform into acute myeloid leukemia (AML) in about 10% and 50% of patients, respectively. However, how additional events cooperate with Ras to promote this transformation are largely unknown. We show that absence of the ubiquitin-specific peptidase 22 (USP22), a component of the Spt-Ada-GCN5-acetyltransferase chromatin-remodeling complex that is linked to cancer progression, unexpectedly promotes AML transformation in mice expressing oncogenic Kras(G12D/+) USP22 deficiency in Kras(G12D/+) mice resulted in shorter survival compared with control mice. This was due to a block in myeloid cell differentiation leading to the generation of AML. This effect was cell autonomous because mice transplanted with USP22-deficient Kras(G12D/+) cells developed an aggressive disease and died rapidly. The transcriptome profile of USP22-deficient Kras(G12D/+) progenitors resembled leukemic stem cells and was highly correlated with genes associated with poor prognosis in AML. We show that USP22 functions as a PU.1 deubiquitylase by positively regulating its protein stability and promoting the expression of PU.1 target genes. Reconstitution of PU.1 overexpression in USP22-deficient Kras(G12D/+) progenitors rescued their differentiation. Our findings uncovered an unexpected role for USP22 in Ras-induced leukemogenesis and provide further insights into the function of USP22 in carcinogenesis. |
