Discussion
Molecular mechanisms involved in leukemogenesis, such as structural
chromosomal rearrangements, alternative splicing, and epigenetic
deregulation can alter the expression of transcripts that are associated
with the B-ALL development. Identifying these mechanisms through
molecular diagnostic technologies will provide a better understanding of
the disease pathogenesis, leading to the rapid expansion of molecular
biomarkers related to B-ALL. Identification of these novel biomarkers
can improve the precision of risk diagnosis, personalized treatment,
better monitoring of treatment response, development of new risk-adapted
targeted therapies, and patient outcome .
This study aimed to evaluate the transcriptome profile of B-ALL patients
to find a novel diagnostic or prognostic biomarker through RNA-seq data
analysis. The differential expression analysis, WGCNA, and GO analysis
was performed to identify patterns of gene expression alterations and
biological pathways related to DEGs. Our first findings
demonstrated the SPRING1 upregulation in B-ALL patients based on
WGCNA analysis and qRT-PCR. Moreover, there was a positive correlation
between the lipopolysaccharide-mediated signaling pathway andSPRING1 activity based on GO enrichment analysis. These data
propose that SPRING1 has an imminent role in B-ALL tumorigenesis
and can be a potential diagnostic marker for this disease. This
integrated approach which includes a combination of bioinformatics and
experimental validation, could be a powerful strategy to identify
potential biomarkers and increase our understanding of the underlying
biology of B-ALL.
Lipid rafts serve as a principal modality for signaling in cancer cells,
where cholesterol assumes a pivotal function in this context.
Accordingly, targeting cholesterol metabolism may be used as a viable
therapeutic approach for the treatment of B-ALL . It is noteworthy that
the disruption of cholesterol metabolism may lead to the formation of
malignancy, such as breast, prostate, and colorectal cancers;
consequently, there is a positive correlation between the cholesterol
levels and cancer incidence . SPRING1 protein (or C12orf49) is localized
in the Golgi and plays a crucial role in regulation of fatty acid
metabolism and tumor pathogenesis (18,19). SPRING1 binds to the
peptidase-site membrane-bound transcription factor 1 (MBTPS1) and
triggers the cleavage of its substrate, specifically sterol regulatory
element binding protein (SREBP) transcription factors (19,21,22).SPRING1 plays a key role in the activation and cleavage of the
SREBP precursor protein through the protease activity and maturation of
S1P during its transport from the endoplasmic reticulum to the Golgi .
Therefore, SPRING1 is essential for maintaining both precursor
and mature SREBP protein levels . SREBPs, as a large class of
transcription factors, regulate lipid homeostasis by modulating the
expression of enzymes necessary for endogenous cholesterol, fatty acid
(FA), triacylglycerol, and phospholipid synthesis . Activation of SREBP
occurs through its transport from the endoplasmic reticulum to the
Golgi, where the S1P enzyme cleaves the endoplasmic reticulum loop of
SREBP . It has been reported that S1P cleavage activity depends on its
interaction with SPRING1 . Moreover, SREBPs transcription factors
regulate cholesterol biosynthesis and uptake for cellular function .
Cholesterol is a major component of membrane lipids, which plays a
critical role in cancer development as the primary platform in the
membrane for signaling regulation in cancer . Consequently, regulation
of membrane cholesterol balance is essential to maintain cellular
homeostasis. Dysregulation of SPRING1 leads to unbalanced
cholesterol metabolism and the possibility of some disorders, such as
tumor formation, cardiovascular, and neurodegenerative diseases .
It has been reported that the function of SPRING1 is associated
with divergent prognostic outcomes across various tumor types, including
kidney, breast, liver, and sarcoma by The Cancer Genome Atlas (TCGA)
database analysis . The upregulation of SPRING1 was indicated in
CRC tissues compared to non-cancerous tissue samples that correlated to
tumor growth. Therefore, SPRING1 was identified as a potential
biomarker that provides therapeutic benefits for CRC patients .
Moreover, the overexpression of SPRING1 in breast cancer tissues
was associated with significantly reduced survival rates of the patients
as demonstrated by TCGA database analysis . Additionally, the
significant upregulation of SPRING1 was confirmed in clear cell
renal cell carcinoma-small renal masses (ccRCC-SRMs) compared to renal
oncocytoma, which was associated with decreased overall survival rate of
patients based on proteome analysis . Consistent with previous studies,
our data showed significant overexpression of SPRING1 in B-ALL
patients. Taken together, our data propound that the SPRING1dysregulation can impact the lipopolysaccharide-mediated signaling
pathway and the downstream genes, which can correlate to B-ALL formation
and development.