Researchers from China have unveiled a novel regulatory pathway in hypocellular myelodysplastic syndromes (MDS), according to a study recently published in the Journal of Pediatric Hematology/Oncology.
The study revealed an intricate interplay between the janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway, the CSN5 gene (encoding COP9 signalosome complex subunit 5), and key transcription factors.
Analyzing CD34+ cells isolated from the bone marrow of patients with hypocellular MDS and healthy subjects, the study found MDS cells exhibited reduced proliferation capacity. Notably, more MDS cells lingered in the G2 phase and displayed heightened resistance to apoptosis.
The SPI1/PU.1 transcription factor, which is known to be involved in the cell cycle, was downregulated in patients’ cells. Although the mRNA level of the heat shock factor 1 (HSF1), a transcriptional regulator of SPI1/PU.1, remained steady, the HSF1 protein underwent degradation via ubiquitination.
Read more about MDS etiology
Chromatin immunoprecipitation assays confirmed the inhibition of HSF1 binding to the SPI1/PU.1 promoter region in MDS cells, reinforcing the link between HSF1 expression and deregulated SPI1/PU.1 transcription.
Furthermore, the researchers found diminished CSN5 expression—a ubiquitination regulator—in MDS cells. Also, binding between HSF1 and F-box and WD repeat domain-containing 7 alpha (FBXW7α), a known regulator of HSF1, was increased.
In MDS cells, the levels of phosphorylated STAT3 were downregulated. This reduction impaired STAT3’s ability to bind to CCAAT/enhancer-binding protein beta (C/EBP-ß), which in turn led to a disruption in the binding activity within the CSN5 promoter region.
Hence, the disrupted STAT3 phosphorylation inhibited CSN5 gene transcription, leading to HSF1 deubiquitination and SPI1/PU.1 downregulation.
Conversely, reinstating CSN5 inhibited HSF1 ubiquitination, reinitiating SPI1/PU.1 transcription, upregulating SPI1/PU.1 protein expression, and fostering colony formation in MDS cells.
“Our study was a preclinical research study and may be somewhat limited by the lack of evidence from human bone marrow sections. If clinical investigation validates our hypothesis, CSN5 might be a potent treatment target for MDS patients with hypocellular bone marrow,” the researchers said.
Reference
Yu Z-P, Jian Z-Y, Sun A-N, Chen B-A, Ge Z. The CSN5/HSF/SPI1/PU.1 axis regulates cell proliferation in hypocellular myelodysplastic syndrome patients. J Pediatr Hematol Oncol. Published online August 1, 2023. doi:10.1097/MPH.0000000000002712
