Related Experiment Video
Updated: Mar 11, 2026
Author Spotlight: Advancing the Detection of Low-Frequency Mutations in Cancer Tissues
Published on: August 23, 2024
Aberrant localization of apoptosis protease activating factor-1 in lipid raft sub-domains of diffuse large B cell
Jayshree L Hirpara1,2, Thomas Loh3, Siok Bian Ng4
1Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Abstract:
Resistance to chemotherapy remains a challenge in the clinical management of diffuse B cell lymphomas despite aggressive chemotherapy such as CHOP and monoclonal CD20. Here we provide evidence that the apoptosome adaptor protein, Apaf-1, is mislocalized in primary cells derived from patients with diffuse large B cell lymphomas (DLBCL). Whereas, the total expression of Apaf-1 did not change, its sub-cellular localization was significantly different in DLBCL, compared to T cell lymphomas as well as cells derived from reactive lymphadenopathy biopsies. As expected, Apaf-1 was detected in the cytosolic fractions of non-B cell lymphomas and non-cancerous tissues; however, in B cell derived lymphomas the protein was detected in membrane raft sub-domains rather than the cytosol. Disruption of lipid raft structures resulted in the redistribution of Apaf-1 to the cytosol and restored apoptosis sensitivity of DLBCL. Furthermore, we identified novel small molecule compounds that target DLBCL by promoting Apaf-1 release form lipid rafts via mechanisms that involve an increase in intracellular reactive oxygen species production. Taken together, our results implicate Apaf-1 mislocalization as a potential diagnostic and prognostic marker for DLBCL, and provide a novel therapeutic strategy for circumventing the drug refractory nature of this sub-class of B cell lymphoma.
Insights
Apoptosome adaptor protein Apaf-1 is mislocalized in diffuse large B cell lymphoma (DLBCL) cells, impacting chemotherapy resistance. Targeting Apaf-1 release from lipid rafts offers a novel therapeutic strategy for DLBCL treatment.
Area of Science:
- Cell Biology
- Oncology
- Biochemistry
Background:
- Chemotherapy resistance is a significant challenge in treating diffuse large B cell lymphomas (DLBCL).
- Current treatments like CHOP and CD20 monoclonal antibodies show limitations in overcoming drug resistance.
- Understanding the molecular mechanisms underlying DLBCL drug resistance is crucial for developing new therapies.
Purpose of the Study:
- To investigate the role of the apoptosome adaptor protein, Apaf-1, in the context of DLBCL.
- To explore the sub-cellular localization of Apaf-1 in DLBCL cells and its potential impact on apoptosis.
- To identify novel therapeutic strategies targeting Apaf-1 mislocalization in DLBCL.
Main Methods:
- Analysis of Apaf-1 sub-cellular localization in primary DLBCL cells, T cell lymphomas, and reactive lymphadenopathy biopsies.
- Fractionation of cellular components to isolate cytosolic and membrane raft fractions.
- Disruption of lipid raft structures and assessment of Apaf-1 redistribution and apoptosis sensitivity.
- Identification and characterization of small molecule compounds targeting Apaf-1 release from lipid rafts.
Main Results:
- Apaf-1 is mislocalized to membrane raft sub-domains in DLBCL cells, unlike in non-B cell lymphomas and non-cancerous tissues where it resides in the cytosol.
- Disrupting lipid rafts causes Apaf-1 redistribution to the cytosol, restoring sensitivity to apoptosis in DLBCL cells.
- Novel small molecules were identified that promote Apaf-1 release from lipid rafts, involving increased reactive oxygen species production.
Conclusions:
- Apaf-1 mislocalization is a key feature of DLBCL and may serve as a diagnostic and prognostic marker.
- Targeting Apaf-1 release from lipid rafts presents a promising therapeutic strategy to overcome chemotherapy resistance in DLBCL.
- This research opens new avenues for developing innovative treatments for drug-refractory B cell lymphomas.
More Related Videos
11:39Subcellular Fractionation of Primary Chronic Lymphocytic Leukemia Cells to Monitor Nuclear/Cytoplasmic Protein Trafficking
Published on: October 23, 2019
10:27Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells
Published on: March 9, 2012
