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Identification of proliferative and non-proliferative subpopulations of leukemic cells in CLL.

Cuthill, KM; Zhang, Y; Pepper, A; Boelen, L; Coulter, E; Asquith, B; Devereux, S; Macallan, DC (2022) Identification of proliferative and non-proliferative subpopulations of leukemic cells in CLL. Leukemia, 36 (9). pp. 2233-2241. ISSN 1476-5551 https://doi.org/10.1038/s41375-022-01656-4
SGUL Authors: Macallan, Derek Clive

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Abstract

Pathogenesis in chronic lymphocytic leukemia (CLL) is strongly linked to the potential for leukemic cells to migrate to and proliferate within lymph-nodes. Previous in vivo studies suggest that all leukemic cells participate in cycles of migration and proliferation. In vitro studies, however, have shown heterogeneous migration patterns.To investigate tumor subpopulation kinetics, we performed in vivo isotope-labeling studies in ten patients with IgVH-mutated CLL (M-CLL). Using deuterium-labeled glucose, we investigated proliferation in sub-populations defined by CXCR4/CD5 and surface (sIgM) expression. Mathematical modeling was performed to test the likelihood that leukemic cells exist as distinct sub-populations or as a single population with the same proliferative capacity. Further labeling studies in two patients with M-CLL commencing idelalisib investigated the effect of B-cell receptor (BCR) antagonists on sub-population kinetics.Modeling revealed that data were more consistent with a model comprising distinct sub-populations (p = 0.008) with contrasting, characteristic kinetics. Following idelalisib therapy, similar labeling suppression across all sub-populations suggested that the most proliferative subset is the most sensitive to treatment. As the quiescent sub-population precedes treatment, selection likely explains the persistence of such residual non-proliferating populations during BCR-antagonist therapy. These findings have clinical implications for discontinuation of long-term BCR-antagonist treatment in selected patients.

Item Type: Article
Additional Information: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ © The Author(s) 2022
Keywords: 1103 Clinical Sciences, 1112 Oncology and Carcinogenesis, Immunology
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Leukemia
ISSN: 1476-5551
Language: eng
Dates:
DateEvent
September 2022Published
28 July 2022Published Online
12 July 2022Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
15012Blood Cancer UKhttp://dx.doi.org/10.13039/501100015570
PubMed ID: 35902732
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/114624
Publisher's version: https://doi.org/10.1038/s41375-022-01656-4

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