Proteomics

Dataset Information

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FBXO9 in Murine Inversion 16 AML


ABSTRACT: The hematopoietic system is maintained throughout life by hematopoietic stem cells that are capable of differentiation to all hematopoietic lineages. An intimate balance between self-renewal, differentiation, and quiescence is required to maintain hematopoiesis. Disruption of this balance can result in hematopoietic malignancy, including acute myeloid leukemia (AML). FBXO9, from the F-box ubiquitin E3 ligases, is down-regulated in patients with AML compared to normal bone marrow. FBXO9 is a substrate recognition component of the Skp1-Cullin-F-box (SCF)-type E3 ligase complex. FBXO9 is highly expressed in hematopoietic stem and progenitor populations, which contain the tumor-initiating population in AML. In AML patients, decrease in FBXO9 expression is most pronounced in patients with the inversion of chromosome 16 (Inv(16)), a rearrangement that generates the transcription factor fusion gene, CBFB-MYH11. To study FBXO9 in malignant hematopoiesis, we generated a conditional knockout mouse model using a novel CRISPR/Cas9 strategy. Our data shows that deletion of Fbxo9 in mice expressing Cbfb-MYH11 leads to markedly accelerated and aggressive leukemia development. In addition, we find loss of FBXO9 leads to increased proteasome expression and tumors are more sensitive to bortezomib suggesting that FBXO9 expression may predict patient response to bortezomib treatment.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spleen, Myeloid Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Samantha Swenson  

LAB HEAD: Shannon Mychel Buckley

PROVIDER: PXD014387 | Pride | 2019-11-27

REPOSITORIES: Pride

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Publications

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

Hynes-Smith R Willow RW   Swenson Samantha A SA   Vahle Heather H   Wittorf Karli J KJ   Caplan Mika M   Amador Catalina C   Hyde R Katherine RK   Buckley Shannon M SM  

Cancers 20191103 11


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. <i>FBXO9</i>, the substrate recognition component from the SCF E3 ubiquitin ligase family, is downregulated in patients with acute myeloid leukemia (AML) compared to healthy bone  ...[more]

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