Biology subjects

Marella, N.

Publications and source records attributed to Marella, N..

2 recordsLinked to original sources

bioRxiv2024

Multi-omics data integration reveals molecular mechanisms of carfilzomib resistance in multiple myeloma

Multiple myeloma represents a complex hematological malignancy, characterized by its wide array of genetic and clinical events. The introduction of proteasome inhibitors, such as carfilzomib or bortezomib, into the therapeutic landscape has notably enhanced the quality of life and survival rates for patients suffering from this disease. Nonetheless, a significant obstacle in the long-term efficacy of this treatment is the inevitable development of resistance to PIs, posing a substantial challenge in managing the disease effectively. Our study investigates the molecular mechanisms behind carfilzomib resistance by analyzing multi-omics profiles from four multiple myeloma cell lines: AMO-1, KMS-12-PE, RPMI-8226 and OPM-2, together with their carfilzomib-resistant variants. We uncovered a significant downregulation of metabolic pathways linked to strong mitochondrial dysfunction in resistant cells. Further examination of patient samples identified key genes - ABCB1, RICTOR, PACSIN1, KMT2D, WEE1 and GATM - potentially crucial for resistance, guiding us towards promising carfilzomib combination therapies to circumvent resistance mechanisms. The response profiles of tested compounds have led to the identification of a network of gene interactions in resistant cells. We identified two already approved drugs, benidipine and tacrolimus, as potential partners for combination therapy with carfilzomib to counteract resistance. This discovery enhances the clinical significance of our findings.

cancer biology↗

bioRxiv2024

Spermidine/spermine N1-acetyltransferase controls tissue-specific regulatory T cell function in chronic inflammation

Regulatory T cells (Tregs) are a critical immune component guarding against excessive inflammatory responses. During chronic inflammation, Tregs fail to control effector T cell responses. The causes of Treg dysfunction in these diseases are poorly characterized and therapies are aimed at blocking aberrant effector responses rather than rescuing Treg function. Here we utilized single-cell RNA sequencing data from patients suffering from chronic skin and colon inflammation to uncover SAT1, the gene encoding spermidine/spermine N1-acetyltransferase (SSAT), as a novel marker and driver of skin-specific Treg dysfunction during TH17-mediated inflammation. Tregs expressing SAT1 exhibit a tissue-specific inflammation signature and show a proinflammatory effector-like profile. In CRISPRa on healthy human skin-derived Tregs increased expression of SAT1 leads to a loss of suppressive function and a switch to a TH17-like phenotype. This phenotype is induced by co-receptor expression on keratinocytes exposed to a TH17 microenvironment. Finally, the potential therapeutic impact of targeting SSAT was demonstrated in a mouse model of skin inflammation by inhibiting SSAT pharmacologically, which rescued Treg number and function in the skin and systemically. Together, these data show that SAT1 expression has severe functional consequences on Tregs and provides a novel target to treat chronic inflammatory skin disease.

immunology↗