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

摘要: Spontaneous regression is a recognized phenomenon in chronic lymphocytic leukemia (CLL) but its biological basis remains unknown. We undertook detailed investigation of the and clinical features 20 spontaneous CLL cases incorporating phenotypic, functional, transcriptomic, 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. also displayed low Ki-67, CD49d, cell-surface immunoglobulin M (IgM) expression IgM-signaling response high CXCR4 expression, proliferative activity associated poor migration proliferation centers, these becoming increasingly marked during regression. Spontaneously transcriptome profile characterized by downregulation metabolic processes as well MYC downstream targets compared CLL. Moreover, was reversal T-cell exhaustion including reduced programmed cell death 1 increased Interestingly, archetypal aberrations HIST1H1B TP53 mutations del(13q14) found some regressing tumors, genetic composition remained stable Conversely, single case relapse following BCR signaling, proliferation, clonal evolution. These observations indicate that appear undergo period before entering more quiescent state, complex interaction between alterations microenvironment determines disease course. Together, findings provide novel insight into underpinning regression, implications for treatment.