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

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 malig...

Full description

Saved in:
Bibliographic Details
Published in:Cancers 2019-11, Vol.11 (11), p.1717
Main Authors: Hynes-Smith, R Willow, Swenson, Samantha A, Vahle, Heather, Wittorf, Karli J, Caplan, Mika, Amador, Catalina, Hyde, R Katherine, Buckley, Shannon M
Format: Article
Language:English
Subjects:
Acute myeloid leukemia
Bone marrow
Bortezomib
Cell cycle
Cell differentiation
Cell self-renewal
CRISPR
Hemopoiesis
Kinases
Leukemia
Mass spectroscopy
Medical prognosis
Metastases
Molecular weight
Mutation
Myeloid leukemia
Patients
Pediatrics
Progenitor cells
Proteasomes
Proteins
Stem cell transplantation
Tumors
Ubiquitin
Ubiquitin-protein ligase
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. , 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 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 highly express proteins associated with metastasis and invasion as well as components of the ubiquitin proteasome system. We confirmed that the loss of leads to increased proteasome activity and tumors cells were more sensitive to in vitro proteasome inhibition with bortezomib, suggesting that expression may predict patients' response to bortezomib.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers11111717