Surveying the landscape of emerging and understudied cell death mechanisms.
Biochimica et biophysica acta. Molecular cell research
Cell death can be a highly regulated process. A large and growing number of mammalian cell death mechanisms have been described over the past few decades. Major pathways with established roles in normal or disease biology include apoptosis, necroptosis, pyroptosis and ferroptosis. However, additional non-apoptotic cell death mechanisms with unique morphological, genetic, and biochemical features have also been described. These mechanisms may play highly specialized physiological roles or only become activated in response to specific lethal stimuli or conditions. Understanding the nature of these emerging and understudied mechanisms may provide new insight into cell death biology and suggest new treatments for diseases such as cancer and neurodegeneration.
View details for DOI 10.1016/j.bbamcr.2023.119432
View details for PubMedID 36690038
Forging a path toward a more sustainable laboratory.
Trends in biochemical sciences
2023; 48 (1): 5-8
Scientific discovery has advanced human society in countless ways, but research requires the expenditure of energy and resources. This Scientific Life article details one laboratory's efforts to reduce the environmental impact of wet-lab research and provides a series of resources to improve lab sustainability.
View details for DOI 10.1016/j.tibs.2022.09.001
View details for PubMedID 36563657
A Novel Cell Death Mechanism Involving the Sphingosine-to-Glycerophospholipid Pathway.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
2022; 36 Suppl 1
Apoptosis is the most well-studied form of cell death, but there exist other cell death pathways that also have roles in normal physiology and disease. It is unclear what other forms of cell death remain to be discovered and how these pathways could inform our understanding of cell and molecular biology. Caspase-independent lethal 56 (CIL56) is a compound that kills cells via a novel cell death mechanism. We conducted a genome-wide CRISPR screen to identify novel regulators of this death pathway. From the screen, we identified trans-2-enoyl-CoA reductase (TECR) as a key regulator of CIL56-induced death. TECR is localized to the endoplasmic reticulum and is required for very long-chain fatty acid (VLCFA) synthesis. When the gene encoding TECR is disrupted, cells become resistant to CIL56-induced death. We find that VLCFA synthesis is dispensable for CIL56-induced death. On the contrary, TECR has a non-canonical role in the conversion of sphingosine to palmitate in the sphingosine-to-glycerophospholipid pathway. Through chemical complementation analyses, we find that this pathway is important for death induction by CIL56. It remains unclear how this pathway could be acting to execute cell death. It is known that palmitate produced in the endoplasmic reticulum can be incorporated into ceramide species, which have long been associated with cell death. Preliminary lipidomic analyses reveal a dramatic increase in palmitoyl-ceramide upon CIL56 treatment. We are investigating the role of this species in CIL56-induced cell death to further characterize the mechanism of death and its importance.
View details for DOI 10.1096/fasebj.2022.36.S1.R2783
View details for PubMedID 35556625
Clonal architecture predicts clinical outcomes and drug sensitivity in acute myeloid leukemia.
1800; 12 (1): 7244
The impact of clonal heterogeneity on disease behavior or drug response in acute myeloid leukemia remains poorly understood. Using a cohort of 2,829 patients, we identify features of clonality associated with clinical features and drug sensitivities. High variant allele frequency for 7 mutations (including NRAS and TET2) associate with dismal prognosis; elevated GATA2 variant allele frequency correlates with better outcomes. Clinical features such as white blood cell count and blast percentage correlate with the subclonal abundance of mutations such as TP53 and IDH1. Furthermore, patients with cohesin mutations occurring before NPM1, or transcription factor mutations occurring before splicing factor mutations, show shorter survival. Surprisingly, a branched pattern of clonal evolution is associated with superior clinical outcomes. Finally, several mutations (including NRAS and IDH1) predict drug sensitivity based on their subclonal abundance. Together, these results demonstrate the importance of assessing clonal heterogeneity with implications for prognosis and actionable biomarkers for therapy.
View details for DOI 10.1038/s41467-021-27472-5
View details for PubMedID 34903734
Preferential targeting of MCL-1 by a hydrocarbon-stapled BIM BH3 peptide.
2019; 10 (58): 6219-6233
BCL-2 family proteins are central regulators of apoptosis and represent prime therapeutic targets for overcoming cell death resistance in malignancies. However, plasticity of anti-apoptotic members, such as MCL-1, often allows for a switch in cell death dependency patterns that lie outside the binding profile of targeted BH3-mimetics. Therefore discovery of therapeutics that effectively inactivate all anti-apoptotic members is a high priority. To address this we tested the potency of a hydrocarbon stapled BIM BH3 peptide (BIM SAHB A ) to overcome both BCL-2 and MCL-1 apoptotic resistance given BIM's naturally wide ranging affinity for all BCL-2 family multidomain members. BIM SAHB A effectively killed diffuse large B-cell lymphoma (DLBCL) cell lines regardless of their anti-apoptotic dependence. Despite BIM BH3's ability to bind all BCL-2 anti-apoptotic proteins, BIM SAHB A 's dominant intracellular target was MCL-1 and this specificity was exploited in sequenced combination BH3-mimetic treatments targeting BCL-2, BCL-XL, and BCL-W. Extending this MCL-1 functional dependence, mouse embryonic fibroblasts (MEFs) deficient in MCL-1 were resistant to mitochondrial changes induced by BIM SAHB A . This study demonstrates the importance of understanding BH3 mimetic functional intracellular affinities for optimized use and highlights the diagnostic and therapeutic promise of a BIM BH3 peptide mimetic as a potential MCL-1 inhibitor.
View details for DOI 10.18632/oncotarget.27262
View details for PubMedID 31692812
View details for PubMedCentralID PMC6817437