Format

Send to

Choose Destination
Blood. 2020 Feb 6;135(6):411-428. doi: 10.1182/blood.2019001262.

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

Author information

1
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
2
Centre for Clinical Haematology, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.
3
Haematological Malignancy Diagnostic Service, St. James's University Hospital, Leeds, United Kingdom.
4
Centre for Computational Biology, University of Birmingham, Birmingham, United Kingdom.
5
Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
6
Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom.
7
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.
8
Department of Haematology, Pinderfields General Hospital, Wakefield, United Kingdom.
9
Department of Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom; and.
10
Section of Experimental Haematology, University of Leeds, Leeds, United Kingdom.

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 time points. All spontaneously regressed tumors were IGHV-mutated with no restricted IGHV usage or B-cell receptor (BCR) stereotypy. They exhibited shortened telomeres similar to nonregressing CLL, indicating prior proliferation. They also displayed low Ki-67, CD49d, cell-surface immunoglobulin M (IgM) 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 with nonregressing CLL. Moreover, spontaneous regression was associated with reversal of T-cell exhaustion features including reduced programmed cell death 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 the microenvironment determines disease course. Together, the findings provide novel insight into the biological processes underpinning spontaneous CLL regression, with implications for CLL treatment.

PMID:
31794600
DOI:
10.1182/blood.2019001262

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center