Exploring the pathways to chronic lymphocytic leukemia
Exploring the pathways to chronic lymphocytic leukemia
In chronic lymphocytic leukemia (CLL), increasing knowledge of the biology of the tumor cells has led to transformative improvements in our capacity to assess and treat patients. The dependence of tumor cells on surface immunoglobulin receptor signaling, survival pathways, and accessory cells within the microenvironment has led to a successful double-barreled attack with designer drugs. Studies have revealed that CLL should be classified based on the mutational status of the expressed IGHV sequences into 2 diseases, either unmutated (U) or mutated (M) CLL, each with a distinctive cellular origin, biology, epigenetics/genetics, and clinical behavior. The origin of U-CLL lies among the natural antibody repertoire, and dominance of IGHV1-69 reveals a superantigenic driver. In both U-CLL and M-CLL, a calibrated stimulation of tumor cells by self-antigens apparently generates a dynamic reiterative cycle as cells, protected from apoptosis, transit between blood and tissue sites. But there are differences in outcome, with the balance between proliferation and anergy favoring anergy in M-CLL. Responses are modulated by an array of microenvironmental interactions. Availability of T-cell help is a likely determinant of cell fate, the dependency on which varies between U-CLL and M-CLL, reflecting the different cells of origin, and affecting clinical behavior. Despite such advances, cell-escape strategies, Richter transformation, and immunosuppression remain as challenges, which only may be met by continued research into the biology of CLL.
827-835
Stevenson, Freda
ba803747-c0ac-409f-a9c2-b61fde009f8c
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Kipps, Thomas J
0fd44186-1f31-4fc9-aa1e-c7bcf9094258
9 September 2021
Stevenson, Freda
ba803747-c0ac-409f-a9c2-b61fde009f8c
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Kipps, Thomas J
0fd44186-1f31-4fc9-aa1e-c7bcf9094258
Stevenson, Freda, Forconi, Francesco and Kipps, Thomas J
(2021)
Exploring the pathways to chronic lymphocytic leukemia.
Blood, 138 (10), .
(doi:10.1182/blood.2020010029).
Abstract
In chronic lymphocytic leukemia (CLL), increasing knowledge of the biology of the tumor cells has led to transformative improvements in our capacity to assess and treat patients. The dependence of tumor cells on surface immunoglobulin receptor signaling, survival pathways, and accessory cells within the microenvironment has led to a successful double-barreled attack with designer drugs. Studies have revealed that CLL should be classified based on the mutational status of the expressed IGHV sequences into 2 diseases, either unmutated (U) or mutated (M) CLL, each with a distinctive cellular origin, biology, epigenetics/genetics, and clinical behavior. The origin of U-CLL lies among the natural antibody repertoire, and dominance of IGHV1-69 reveals a superantigenic driver. In both U-CLL and M-CLL, a calibrated stimulation of tumor cells by self-antigens apparently generates a dynamic reiterative cycle as cells, protected from apoptosis, transit between blood and tissue sites. But there are differences in outcome, with the balance between proliferation and anergy favoring anergy in M-CLL. Responses are modulated by an array of microenvironmental interactions. Availability of T-cell help is a likely determinant of cell fate, the dependency on which varies between U-CLL and M-CLL, reflecting the different cells of origin, and affecting clinical behavior. Despite such advances, cell-escape strategies, Richter transformation, and immunosuppression remain as challenges, which only may be met by continued research into the biology of CLL.
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Accepted/In Press date: 5 May 2021
Published date: 9 September 2021
Additional Information:
Funding Information:
This work was supported by Blood Cancer UK/Bloodwise (grant 18009); the National Institutes of Health, National Cancer Institute (R01-CA236361) (T.J.K.); the Keanu Eyles Hematology Fellowship; the Cancer Research UK ECRIN-M3 program (grant C42023/A29370); the CRUK CLL program (C2750/A23669); and CRUK Southampton Centre core funding (C36811/A29101).
Publisher Copyright:
© 2021 American Society of Hematology
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Local EPrints ID: 453375
URI: http://eprints.soton.ac.uk/id/eprint/453375
ISSN: 0006-4971
PURE UUID: f66376ac-2c7f-414d-9123-e094a6e713cf
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Date deposited: 13 Jan 2022 18:16
Last modified: 17 Mar 2024 06:53
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Thomas J Kipps
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