Abstract
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.
Highlights
Acute myeloid leukemia (AML) is a hematologic malignancy resulting in an accumulation of immature myeloid blasts that impair normal hematopoiesis [1]
To identify F-box proteins involved in the initiation and/or progression of acute myeloid leukemia (AML), we analyzed patient data from the Microarray Innovations in LEukemia (MILE) study for expression of 61 F-box proteins (GSE13159) [26]
We have identified Fbxo9 as a tumor suppressor of AML and shown that loss of its expression leads to increased proteasome activity and sensitivity to proteasome inhibition, implying that FBXO9 expression could be used as a biomarker to identify patients who would respond well to proteasome inhibition
Summary
Acute myeloid leukemia (AML) is a hematologic malignancy resulting in an accumulation of immature myeloid blasts that impair normal hematopoiesis [1]. This disease accounts for 35% of new leukemia diagnoses and 48% of leukemia-related deaths [2]. New therapies have recently been approved, they are limited to specific subtypes of AML and only increase the treatment options for limited subsets of patients [3,4,5,6]. One system that has not been extensively studied in the context of AML is the ubiquitin proteasome system (UPS). The UPS coordinates the degradation of proteins globally and compartmentally
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