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Gene & Protein in Disease A pyroptosis-related gene signature in myeloma

it a relatively rare cancer. Despite being rare, MM of pyroptosis also opens a new avenue for the development
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accounts for a significant proportion of deaths related of therapeutic strategies. For example, modulating
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to hematological malignancies. The American Cancer pyroptosis may enhance the efficacy of immunotherapies
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Society website (https://www.cancer.org/cancer/types/ in cancer. Despite these advances, many questions
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multiple-myeloma/about/key-statistics.html) reports that remain to be answered. For instance, the regulation of
there are an estimated 35,780 new myeloma cases and gasdermin proteins and the role of pyroptosis in non-
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approximately 12,540 myeloma-associated deaths in 2024. pathogenic conditions are not fully understood. Future
Recently, significant strides have been made in both the research will likely focus on these areas and on translating
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understanding and management of MM. Last decade has the knowledge of pyroptosis into clinical applications.
seen significant advancements in treatment against MM. Recent research has suggested a possible interplay
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In addition, the advent of next-generation sequencing has between MM and pyroptosis, opening a promising avenue
provided insights into the molecular heterogeneity of MM, for novel therapeutic strategies. Pyroptosis, through
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leading to the identification of high-risk subgroups and the the elimination of cancerous cells and the initiation of
development of more personalized treatment strategies. an immune response, could be leveraged to enhance the
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According to the Revised-International Staging System efficacy of existing MM treatments. Identifying prognostic
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(R-ISS) guideline, MM patients are mainly stratified into 4 biomarkers of pyroptosis in MM holds substantial potential
risk categories, with a homogeneous repatrition, and those to improve patient outcomes. Such biomarkers could not
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with chromosomal alterations, including del(17p), t(4;14), only provide insights into a patient’s likely disease course,
t(14;16), t(14;20), gain(1q), and or gene mutations such aiding in risk stratification and personalized treatment
as p53 mutation, are labeled as having poor prognosis or planning, but also reveal novel targets for therapy. In
high-risk outcomes. The disease with two or more high risk particular, they could identify patients who might benefit
factors is regarded as a double- or multiple-hit myeloma, from therapies that modulate pyroptosis, providing a new
which may translate to poorer outcomes in the affected approach to combat this not-yet-curable disease. Hence,
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patients. However, MM remains a largely incurable while the path to fully understanding the role of pyroptosis
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disease, with most patients experiencing relapse after in MM is undoubtedly challenging, it is one that holds
initial response to therapy due to genetic heterogeneity. immense promise for improving the lives of those affected
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Interestingly, in addition to traditional chromosomal by this pathological condition. 7
translocations and gene mutations, increased lactate
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dehydrogenase (LDH) concentration is also taken into Wang et al. developed a prognostic risk scoring model
consideration in the R-ISS. LDH is an important enzyme based on 11 pyroptosis-related genes (PRGs) from the
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of the anaerobic metabolic pathway, and it is present in all GSE136324 dataset. However, the small validation cohort
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tissues and increased in the blood levels when tissues and might affect the reliability of their findings. Zhang et al.
cells are injured. LDH is not only a hallmark checkpoint of established a prognostic model using 9 out of 33 candidate
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gluconeogenesis and DNA metabolism, but also associated PRGs, but their model lacked experimental validation.
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with cell death, such as cell pyroptosis. In our recent study, Li et al. proposed a 6-gene signature but it could not
we found that LDH is strikingly increased when MM cells distinguish between disease subgroups in the validation
undergo pyroptosis. 11 dataset. In the present study, we conducted comparisons
between MM patients and healthy controls using a larger
Pyroptosis acts as a defense mechanism against sample dataset, and based on our results, we identified
microbial infections. It typically manifests as cell swelling, a novel and comprehensive PRG signature that can
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membrane rupture, and the release of pro-inflammatory effectively classify MM patients according to disease risk.
intracellular contents, leading to an inflammatory
response. Over the past decade, our understanding of the 2. Materials and methods
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molecular mechanisms behind pyroptosis has significantly
advanced. It is now known that pyroptosis is mediated by 2.1. Data sources and processing
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a family of proteins called gasdermins, which are capable The clinical data and PRGs of 859 MM patients were
of forming pores in the cell membrane. Pyroptosis is retrieved from the Cancer Genome Atlas (TCGA)-
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increasingly recognized as playing crucial roles in various MMRF CoMMpass project. The gene expression data
diseases. In infectious diseases, pyroptosis can eliminate were standardized using the “limma” package, a scaling
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the intracellular replication niches of pathogens and method to maintain data integrity and comparability.
amplify the host immune response. In the context of Patients lacking clinical information (n = 17) were
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cancer, it can either inhibit or promote tumor growth, excluded, resulting in 842 MM patients being eligible. The
contingent on the particular circumstances. The discovery “caret” package was employed to divide these patients into
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Volume 3 Issue 4 (2024) 2 doi: 10.36922/gpd.4534