dc.description.abstract
T-cell acute leukaemia (T-ALL) is a haematological cancer disease, resulting from the malignant
transformation of T-progenitor cells [1]. Currently, up to 85 % of the patients achieve 5-year survival
rates without relapse with the state-of-the-art procedure. However, if individual cancer cells withstand
the initial treatment (persister cells) and the cancer relapses, successive therapies are less effective
and the survival rate decreases below 25 % [2]. Drug-resistant cells also pose a serious problem for
long-term recovery [3].
Investigations established that this cell type, particularly in a mesenchymal state or close to metastasis,
exhibits problems in regulating its inner ROS production and is more susceptible to ferroptosis. This
regulated, non-apoptotic cell death is initiated by iron-mediated phospholipid peroxidation through
increased reactive oxygen radical production, via various cell metabolism pathways. As a consequence,
a small increase in ROS production will push those cells to rapidly enter ferroptosis. By artificially
increasing the ROS production in those T-cells, the utilisation of this mechanism to eliminate refractory
cancer cells could represent a new generation of cancer therapeutics [4].
The actual chemical “point of no return” responsible for ferroptosis-cell death is yet unknown. It is
confirmed that uncontrolled peroxidation of phospholipids plays a crucial role in cell degradation and
may be associated with nanoscale hotspots of peroxidised phospholipids causing membrane damage,
lipid cross-linking to limit membrane fluidity or impairing membrane integrity by pore formation [4].
The use of atomic force microscopy coupled with infrared spectroscopy (AFM-IR) allows the
investigation of spectra-structure correlations in the mid-IR spectral range at nanoscale to achieve
chemical identification of these ferroptosis-induced membrane changes.
Investigations were performed on an immortal cell line (Jurkat) spiked with two known ferroptosis
inducing reagents (APR-246, RSL3) to initiate cell death. The paraformaldehyde-fixed cells were
analysed for the appearance of carbonyl ester bands of various oxidized lipid peroxidation end
products in the membranes.
A better understanding of the degradation processes caused by ferroptosis at the nanoscale could
contribute to a better perception of this outstanding mechanism and the development of future
therapeutics.
[1] P. Van Vlierberghe and A. Ferrando, ‘The molecular basis of T cell acute lymphoblastic leukemia’,
J. Clin. Invest., vol. 122, no. 10, pp. 3398–3406, Oct. 2012, doi: 10.1172/JCI61269.
[2] E. A. Raetz and D. T. Teachey, ‘T-cell acute lymphoblastic leukemia’, Hematology, vol. 2016, no. 1,
pp. 580–588, Dec. 2016, doi: 10.1182/asheducation-2016.1.580.
[3] R. Rodriguez, S. L. Schreiber, and M. Conrad, ‘Persister cancer cells: Iron addiction and vulnerability
to ferroptosis’, Molecular Cell, vol. 82, no. 4, pp. 728–740, Feb. 2022, doi:
10.1016/j.molcel.2021.12.001.
[4] X. Jiang, B. R. Stockwell, and M. Conrad, ‘Ferroptosis: mechanisms, biology and role in disease’,
Nat Rev Mol Cell Biol, vol. 22, no. 4, pp. 266–282, Apr. 2021, doi: 10.1038/s41580-020-00324-8.
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