Integrative analysis of spontaneous CLL regression highlights genetic and microenvironmental interdependency in CLL: natural history and mechanism of spontaneous CLL regression

Marwan Cheng Kuang Kwok, Ceri Oldreive, Andy C Rawstron, Anshita Goel, Grigorios Papatzikas, Rhiannon Jones, Samantha Drennan, Angelo Agathanggelou, Archana Sharma-Oates, Paul Evans, Edward Smith, Surita Dalal, Jingwen Mao, Robert Hollows, Naheema Gordon, Mayumi Hamada, Nick Davies, Helen Parry, Andrew Beggs, Talha MunirPaul Moreton, Shankara Paneesha, Guy Pratt, Malcolm Taylor, Francesco Forconi, Duncan Baird, Jean-Baptiste Cazier, Paul Moss, Peter Hillmen, Tatjana Stankovic

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
103 Downloads (Pure)

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, cellsurface 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.

Original languageEnglish
Pages (from-to)411-428
Number of pages18
JournalBlood
Volume135
Issue number6
Early online date3 Dec 2019
DOIs
Publication statusPublished - 6 Feb 2020

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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