The impact of multiple myeloma and carfilzomib on the endothelium
File(s)
Author(s)
Huladar, Shadi
Type
Thesis
Abstract
Background: Multiple myeloma (MM) is associated with one of the highest rates of
venous thromboembolism among malignancies, yet the vascular mechanisms
underlying this risk remain incompletely defined. This thesis tests the hypothesis that
MM drives a coordinated program of endothelial activation encompassing thrombosis
and angiogenesis, and evaluates whether the proteasome inhibitor carfilzomib (CFZ)
counteracts this program at the molecular and functional levels. Methods: Plasma from
MM patients and matched controls was analysed for Weibel–Palade body (WPB)–derived
proteins, including von Willebrand factor (VWF), angiopoietin-2, osteoprotegerin, and IL-
8, alongside VWF multimer structure and angiogenic activity. Endothelial cells were
exposed to MM cell line–derived conditioned media, with functional assessment by
ELISA, shear-dependent VWF–platelet string assays, Matrigel tube formation, and RNA
sequencing. Transcriptomic analysis combined curated endothelial gene panels,
differential expression, gene set enrichment, and GO/Reactome pathway analysis to
define network-level responses. CFZ was assessed for its ability to modulate MM-
induced endothelial activation. Results: MM patient plasma exhibited elevated WPB-
derived proteins, enrichment of high-molecular-weight VWF multimers, and increased
angiogenic potential, indicating systemic endothelial activation. MM-conditioned media
induced VWF secretion, platelet-decorated VWF strings under flow, and robust
endothelial sprouting. Transcriptomic profiling revealed coherent endothelial programs
enriched for angiogenesis, coagulation, inflammatory signalling, extracellular matrix
remodelling, and metabolic reprogramming. In contrast, CFZ consistently suppressed
MM-associated angiogenic and inflammatory gene networks while inducing proteostatic
and protein quality-control pathways. GO and Reactome analyses confirmed a shift
toward endothelial quiescence, characterised by enhanced ubiquitin–proteasome
regulation and attenuation of vascular activation modules. Conclusion: MM induces a
coordinated pro-thrombotic and pro-angiogenic endothelial state through network-level
transcriptional reprogramming. CFZ exerts a robust counter-regulatory effect by
suppressing pathological vascular activation and reinforcing endothelial homeostasis,
positioning endothelial signalling pathways as key therapeutic targets in mitigating MM-
associated vascular complications.
venous thromboembolism among malignancies, yet the vascular mechanisms
underlying this risk remain incompletely defined. This thesis tests the hypothesis that
MM drives a coordinated program of endothelial activation encompassing thrombosis
and angiogenesis, and evaluates whether the proteasome inhibitor carfilzomib (CFZ)
counteracts this program at the molecular and functional levels. Methods: Plasma from
MM patients and matched controls was analysed for Weibel–Palade body (WPB)–derived
proteins, including von Willebrand factor (VWF), angiopoietin-2, osteoprotegerin, and IL-
8, alongside VWF multimer structure and angiogenic activity. Endothelial cells were
exposed to MM cell line–derived conditioned media, with functional assessment by
ELISA, shear-dependent VWF–platelet string assays, Matrigel tube formation, and RNA
sequencing. Transcriptomic analysis combined curated endothelial gene panels,
differential expression, gene set enrichment, and GO/Reactome pathway analysis to
define network-level responses. CFZ was assessed for its ability to modulate MM-
induced endothelial activation. Results: MM patient plasma exhibited elevated WPB-
derived proteins, enrichment of high-molecular-weight VWF multimers, and increased
angiogenic potential, indicating systemic endothelial activation. MM-conditioned media
induced VWF secretion, platelet-decorated VWF strings under flow, and robust
endothelial sprouting. Transcriptomic profiling revealed coherent endothelial programs
enriched for angiogenesis, coagulation, inflammatory signalling, extracellular matrix
remodelling, and metabolic reprogramming. In contrast, CFZ consistently suppressed
MM-associated angiogenic and inflammatory gene networks while inducing proteostatic
and protein quality-control pathways. GO and Reactome analyses confirmed a shift
toward endothelial quiescence, characterised by enhanced ubiquitin–proteasome
regulation and attenuation of vascular activation modules. Conclusion: MM induces a
coordinated pro-thrombotic and pro-angiogenic endothelial state through network-level
transcriptional reprogramming. CFZ exerts a robust counter-regulatory effect by
suppressing pathological vascular activation and reinforcing endothelial homeostasis,
positioning endothelial signalling pathways as key therapeutic targets in mitigating MM-
associated vascular complications.
Version
Open Access
Date Issued
2025-12-15
Date Awarded
2026-05-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
McKinnon, Tom
Sponsor
Taibah University
Grant Number
WSSU.I36115
Publisher Department
Department of Immunology and Inflammation
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)