Biology subjects

Ali, A. M.

Publications and source records attributed to Ali, A. M..

3 recordsLinked to original sources

bioRxiv2024

Taurine/chenodeoxycholic acid ratio as a circulating biomarker of insidious vitamin B12 deficiency in humans

Deficiency of vitamin B12 (B12), an essential water-soluble vitamin, leads to irreversible neurological damage, osteoporosis, cardiovascular diseases, and anemia. Clinical tests to detect B12deficiency lack specificity and sensitivity. B12 deficiency is thus insidious because progressive decline in organ functions may go unnoticed until the damage is advanced or irreversible. Here, using targeted unbiased metabolomic profiling in the sera of B12-deficient versus control individuals, we set out to identify biomarker(s) of B12 deficiency. Metabolomic profiling identified 77 metabolites, and Partial least squares discriminant-analysis (PLS-DA) and hierarchical clustering analysis (HCA) showed a differential abundance in B12-deficient sera of taurine, xanthine, hypoxanthine, chenodeoxycholic acid, neopterin, and glycocholic acid. Random forest (RF) multivariate analysis identified a taurine/chenodeoxycholic acid ratio, with an AUC score of 1, to be the best biomarker to predict B12 deficiency. Mechanistically, B12 deficiency reshaped the transcriptomic and metabolomic landscape of the cell identifying a downregulation of methionine, taurine, urea cycle, and nucleotide metabolism, and an upregulation of Krebs cycle. Thus, we propose taurine/chenodeoxycholic acid ratio in serum as a potential biomarker of B12 deficiency in humans and elucidate cellular metabolic pathways regulated by B12 deficiency.

pharmacology and toxicology↗

bioRxiv2023

Multiplex Base Editing to Protect from CD33-Directed Therapy: Implications for Immune and Gene Therapy

On-target toxicity to normal cells is a major safety concern with targeted immune and gene therapies. Here, we developed a base editing (BE) approach exploiting a naturally occurring CD33 single nucleotide polymorphism leading to removal of full-length CD33 surface expression on edited cells. CD33 editing in human and nonhuman primate (NHP) hematopoietic stem and progenitor cells (HSPCs) protects from CD33-targeted therapeutics without affecting normal hematopoiesis in vivo, thus demonstrating potential for novel immunotherapies with reduced off-leukemia toxicity. For broader applications to gene therapies, we demonstrated highly efficient (>70%) multiplexed adenine base editing of the CD33 and gamma globin genes, resulting in long-term persistence of dual gene-edited cells with HbF reactivation in NHPs. In vitro, dual gene-edited cells could be enriched via treatment with the CD33 antibody-drug conjugate, gemtuzumab ozogamicin (GO). Together, our results highlight the potential of adenine base editors for improved immune and gene therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/529353v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@70c99dorg.highwire.dtl.DTLVardef@c46ef4org.highwire.dtl.DTLVardef@505fd2org.highwire.dtl.DTLVardef@c30b8c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2020

CK1 Delta Is an mRNA Cap-Associated Protein That Drives Translation Initiation and Tumor Growth

Whether translation is differentially regulated across liquid and solid tumors remains poorly understood. Here we report the discovery that Casein Kinase 1 delta (CK1{delta}) plays a key role in regulating translation initiation in blood cancers, but interestingly, not in solid tumors. In lymphomas CK1{delta} is a key positive regulator of 4E-BP1 and p70S6K phosphorylation, assembly of eIF4F, and translation initiation. Furthermore, CK1{delta} is pulled down by m7GTP-agarose that mimics the mRNA m7G cap, consistent with the regulatory role of CK1{delta} in translation initiation. Targeting CK1{delta} using a small molecule inhibitor, namely SR-3029, potently kills lymphoma cell lines and primary lymphoma cells across histology subtypes. While SR-3029 shares with mTORC1 inhibitors the overlapping mechanism of repressing 4E-BP1 and p70S6K/RPS6 phosphorylation, the kinetics of repression is slow with SR-3029 and fast with mTORC1 inhibitors such as Torin-1. Remarkably, it is slower-acting SR-3029, but not fast-acting Torin-1, that kills lymphoma cells consistently across multiple histology subtypes. Proteomics and RNA sequencing studies show that SR-3029 represses the expression of many genes preferentially at the translation step, such as genes in the reactome translation initiation pathway. SR-3029 markedly represses the protein level of the C-MYC oncogene without decreasing its mRNA level. In contrast, Torin-1 fails to reduce the protein level of C-MYC in the same lymphoma cells. While SR-3029 also demonstrates potent activity in select solid tumors, its mechanism of action in the solid tumors is different. In breast cancer cells SR-3029 inhibits nuclear localization of {beta}-catenin but at the same concentrations does not inhibit 4E-BP1 and p70S6K phosphorylation or global protein synthesis. Likewise, SR-3029 does not inhibit nuclear localization of {beta}-catenin in lymphoma cells. Our results indicate that CK1{delta} is an mRNA cap-associated protein and an upstream kinase required for 4E-BP1 and p70S6K phosphorylation. CK1{delta} stimulates assembly of eIF4F and translation initiation, and is a critical driver for tumor growth in blood cancers across multiple histology types. CK1{delta} invokes the alternative mechanism of regulating {beta}-catenin in select solid tumors. Our results indicate that CK1{delta} inhibition is a promising therapeutic strategy in both liquid and solid tumors, and the distinct roles of CK1{delta} in these malignancies may serve as biomarkers to enable precision cancer treatment.

cancer biology↗