Next Article in Journal
Systematic Review of Irreversible Electroporation Role in Management of Locally Advanced Pancreatic Cancer
Previous Article in Journal
Balancing STAT Activity as a Therapeutic Strategy
 
 
Article

Loss of FBXO9 Enhances Proteasome Activity and Promotes Aggressiveness in Acute Myeloid Leukemia

1
Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
2
Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
3
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
4
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(11), 1717; https://doi.org/10.3390/cancers11111717
Received: 14 October 2019 / Revised: 30 October 2019 / Accepted: 1 November 2019 / Published: 3 November 2019
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’ response to bortezomib. View Full-Text
Keywords: FBXO9; AML; bortezomib; proteasome; E3 ligase; F-Box FBXO9; AML; bortezomib; proteasome; E3 ligase; F-Box
Show Figures

Figure 1

MDPI and ACS Style

Hynes-Smith, R.W.; Swenson, S.A.; Vahle, H.; Wittorf, K.J.; Caplan, M.; Amador, C.; Hyde, R.K.; Buckley, S.M. Loss of FBXO9 Enhances Proteasome Activity and Promotes Aggressiveness in Acute Myeloid Leukemia. Cancers 2019, 11, 1717. https://doi.org/10.3390/cancers11111717

AMA Style

Hynes-Smith RW, Swenson SA, Vahle H, Wittorf KJ, Caplan M, Amador C, Hyde RK, Buckley SM. Loss of FBXO9 Enhances Proteasome Activity and Promotes Aggressiveness in Acute Myeloid Leukemia. Cancers. 2019; 11(11):1717. https://doi.org/10.3390/cancers11111717

Chicago/Turabian Style

Hynes-Smith, R. Willow, Samantha A. Swenson, Heather Vahle, Karli J. Wittorf, Mika Caplan, Catalina Amador, R. Katherine Hyde, and Shannon M. Buckley. 2019. "Loss of FBXO9 Enhances Proteasome Activity and Promotes Aggressiveness in Acute Myeloid Leukemia" Cancers 11, no. 11: 1717. https://doi.org/10.3390/cancers11111717

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop