MDS is a heterogeneous myeloid malignancy characterized by blood cell morphological dysplasia, ineffective clonal hematopoiesis, and risk of transformation to sAML. A number of genetic abnormalities have been identified in MDS and sAML, but sensitive sequencing methods can detect these mutations in nearly all healthy individuals by 60 years of age. Therefore this study was doen to devise sensitive sequencing methods can detect these mutations in nearly all healthy individuals.
CRISPR/Cas9 screen in the human MDS-L cell line was performed for the analysis. Loss of the F-Box protein FBXO11, a component of the SCF ubiquitin ligase complex, confers cytokine independent growth to MDS-L cells, suggesting a tumor suppressor role for FBXO11 in myeloid malignancies. Putative FBXO11 substrates are enriched for proteins with functions in RNA metabolism and, of note, spliceosome mutations that are commonly found in MDS/sAML are rare in patients with low FBXO11 expression.Loss of FBXO11 leads to significant changes in transcriptional pathways influencing leukocyte proliferation, differentiation, and apoptosis. Lastly, FBXO11 expression is reduced in patients with secondary AML.
The findings of this study concluded that loss of FBXO11 is a mechanism for disease transformation of MDS into AML, and may represent a future therapeutic target.
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