Loss of FBXO9 enhances proteasome activity and promotes aggressiveness in acute myeloid leukemia
| Autor: | R. Willow Hynes-Smith, Mika Caplan, Catalina Amador, Shannon M. Buckley, Heather Vahle, Karli J. Wittorf, Samantha A. Swenson, R. Katherine Hyde |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research fbxo9 Population Biology lcsh:RC254-282 Article 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases Conditional gene knockout medicine f-box Progenitor cell education 030304 developmental biology 0303 health sciences education.field_of_study Bortezomib bortezomib Myeloid leukemia e3 ligase lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease 3. Good health Ubiquitin ligase Leukemia Haematopoiesis 030104 developmental biology medicine.anatomical_structure aml proteasome Oncology 030220 oncology & carcinogenesis biology.protein Cancer research Bone marrow Stem cell medicine.drug |
| Zdroj: | Cancers, Vol 11, Iss 11, p 1717 (2019) Cancers Volume 11 Issue 11 |
| DOI: | 10.1101/732198 |
| Popis: | The hematopoietic system is maintained throughout life by stem cells that are capable of differentiating into all hematopoietic lineages. An intimate balance between self-renewal, differentiation, and quiescence is required to maintain hematopoiesis and disruption of this balance can result in malignant transformation. FBXO9, the substrate recognition component from the SCF E3 ubiquitin ligase family, is downregulated in patients with acute myeloid leukemia (AML) compared to healthy bone marrow, and this downregulation is particularly evident in patients with inv(16) AML. To study FBXO9 in malignant hematopoiesis, we generated a conditional knockout mouse model using a novel CRISPR/Cas9 strategy. Deletion of Fbxo9 in the murine hematopoietic system showed no adverse effects on stem and progenitor cell function but in AML lead to markedly accelerated and aggressive leukemia development in mice with inv(16). Not only did Fbxo9 play a role in leukemia initiation but it also functioned to maintain AML activity and promote disease progression. Quantitative mass spectrometry from primary tumors reveals tumors lacking Fbxo9 highly express proteins associated with metastasis and invasion as well as components of the ubiquitin proteasome system. We confirmed that the loss of FBXO9 leads to increased proteasome activity and tumors cells were more sensitive to in vitro proteasome inhibition with bortezomib, suggesting that FBXO9 expression may predict patients&rsquo response to bortezomib. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|