TY - JOUR
T1 - Integrative analysis of spontaneous CLL regression highlights genetic and microenvironmental interdependency in CLL
T2 - natural history and mechanism of spontaneous CLL regression
AU - Kwok, Marwan Cheng Kuang
AU - Oldreive, Ceri
AU - Rawstron, Andy C
AU - Goel, Anshita
AU - Papatzikas, Grigorios
AU - Jones, Rhiannon
AU - Drennan, Samantha
AU - Agathanggelou, Angelo
AU - Sharma-Oates, Archana
AU - Evans, Paul
AU - Smith, Edward
AU - Dalal, Surita
AU - Mao, Jingwen
AU - Hollows, Robert
AU - Gordon, Naheema
AU - Hamada, Mayumi
AU - Davies, Nick
AU - Parry, Helen
AU - Beggs, Andrew
AU - Munir, Talha
AU - Moreton, Paul
AU - Paneesha, Shankara
AU - Pratt, Guy
AU - Taylor, Malcolm
AU - Forconi, Francesco
AU - Baird, Duncan
AU - Cazier, Jean-Baptiste
AU - Moss, Paul
AU - Hillmen, Peter
AU - Stankovic, Tatjana
PY - 2020/2/6
Y1 - 2020/2/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85079102586&partnerID=8YFLogxK
U2 - 10.1182/blood.2019001262
DO - 10.1182/blood.2019001262
M3 - Article
SN - 0006-4971
VL - 135
SP - 411
EP - 428
JO - Blood
JF - Blood
IS - 6
ER -