Loss of FBXO9 enhances proteasome activity and promotes aggressiveness in acute myeloid leukemia

R. Willow Hynes-Smith, Samantha A. Swenson, Heather Vahle, Karli J. Wittorf, Mika Caplan, Catalina Amador, R. Katherine Hyde, Shannon M. Buckley

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number1717
JournalCancers
Volume11
Issue number11
DOIs
StatePublished - Nov 2019

Fingerprint

Proteasome Endopeptidase Complex
Acute Myeloid Leukemia
Hematopoietic System
Stem Cells
Hematopoiesis
Leukemia
SKP Cullin F-Box Protein Ligases
Down-Regulation
Clustered Regularly Interspaced Short Palindromic Repeats
Neoplasms
Ubiquitin-Protein Ligases
Ubiquitin
Knockout Mice
Disease Progression
Mass Spectrometry
Bone Marrow
Neoplasm Metastasis
Proteins
Bortezomib

Keywords

  • AML
  • Bortezomib
  • E3 ligase
  • F-Box
  • FBXO9
  • Proteasome

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Willow Hynes-Smith, R., Swenson, S. A., Vahle, H., Wittorf, K. J., Caplan, M., Amador, C., ... Buckley, S. M. (2019). Loss of FBXO9 enhances proteasome activity and promotes aggressiveness in acute myeloid leukemia. Cancers, 11(11), [1717]. https://doi.org/10.3390/cancers11111717

Loss of FBXO9 enhances proteasome activity and promotes aggressiveness in acute myeloid leukemia. / Willow Hynes-Smith, R.; Swenson, Samantha A.; Vahle, Heather; Wittorf, Karli J.; Caplan, Mika; Amador, Catalina; Katherine Hyde, R.; Buckley, Shannon M.

In: Cancers, Vol. 11, No. 11, 1717, 11.2019.

Research output: Contribution to journalArticle

Willow Hynes-Smith, R, Swenson, SA, Vahle, H, Wittorf, KJ, Caplan, M, Amador, C, Katherine Hyde, R & Buckley, SM 2019, 'Loss of FBXO9 enhances proteasome activity and promotes aggressiveness in acute myeloid leukemia', Cancers, vol. 11, no. 11, 1717. https://doi.org/10.3390/cancers11111717
Willow Hynes-Smith, R. ; Swenson, Samantha A. ; Vahle, Heather ; Wittorf, Karli J. ; Caplan, Mika ; Amador, Catalina ; Katherine Hyde, R. ; Buckley, Shannon M. / Loss of FBXO9 enhances proteasome activity and promotes aggressiveness in acute myeloid leukemia. In: Cancers. 2019 ; Vol. 11, No. 11.
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