Integrative analysis of spontaneous CLL regression highlights genetic and microenvironmental interdependency in CLL.

Kwok, Marwan and Oldreive, Ceri and Rawstron, Andy C and Goel, Anshita and Papatzikas, Grigorios and Jones, Rhiannon E and Drennan, Samantha and Agathanggelou, Angelo and Sharma-Oates, Archana and Evans, Paul and Smith, Edward and Dalal, Surita and Mao, Jingwen and Hollows, Robert and Gordon, Naheema and Hamada, Mayumi and Davies, Nicholas J and Parry, Helen and Beggs, Andrew D and Munir, Talha and Moreton, Paul and Paneesha, Shankara and Pratt, Guy and Taylor, A Malcolm R and Forconi, Francesco and Baird, Duncan M and Cazier, Jean-Baptiste and Moss, Paul and Hillmen, Peter and Stankovic, Tatjana (2019) Integrative analysis of spontaneous CLL regression highlights genetic and microenvironmental interdependency in CLL. Blood. ISSN 1528-0020.

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Official URL: https://ashpublications.org/blood/article-abstract...

Abstract

Spontaneous regression is a recognized phenomenon in chronic lymphocytic leukemia (CLL) but its biological basis remains unknown. We undertook a detailed investigation of the biological and clinical features of 20 spontaneous CLL regression cases incorporating phenotypic, functional, transcriptomic and genomic studies at sequential timepoints. All spontaneously regressed tumors were IGHV-mutated with no restricted IGHV usage or B-cell receptor (BCR) stereotypy. They exhibited shortened telomeres similar to non-regressing CLL indicating prior proliferation. They also displayed low Ki-67, CD49d, sIgM expression and IgM signaling response but high CXCR4 expression indicating low proliferative activity associated with poor migration to proliferation centers, with these features becoming increasingly marked during regression. Spontaneously regressed CLL displayed a transcriptome profile characterized by downregulation of metabolic processes as well as MYC and its downstream targets compared to non-regressing CLL. Moreover, spontaneous regression was associated with reversal of T-cell exhaustion features including reduced PD-1 expression and increased T-cell proliferation. Interestingly, archetypal CLL genomic aberrations including HIST1H1B and TP53 mutations and del(13q14) were found in some spontaneously regressing tumors, but genetic composition remained stable during regression. Conversely, a single case of CLL relapse following spontaneous regression was associated with increased BCR signaling, CLL proliferation and clonal evolution. These observations indicate that spontaneously regressing CLL appear to undergo a period of proliferation before entering a more quiescent state, and that a complex interaction between genomic alterations and microenvironment determines disease course. Together, the findings provide novel insight into the biological processes underpinning spontaneous CLL regression, with implications for CLL treatment.

Item Type: Article
Subjects: QZ Pathology. Oncology
WH Haemic and lymphatic systems. Haematology
Divisions: Planned IP Care > Oncology and Clinical Haematology
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Depositing User: Mrs Yolande Brookes
Date Deposited: 06 Dec 2019 14:31
Last Modified: 06 Dec 2019 14:31
URI: http://www.repository.uhblibrary.co.uk/id/eprint/2661

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