Clonality analysis suggests that early-onset acute lymphoblastic leukaemia is of single-cell origin and implies no major role for germ cell mutations in parents

Abstract

SummaryChildhood leukaemia presenting at a young age has been suspected of resulting from a leukaemogenic mutation in parental germ cells, either spontaneously or due to the exposure of a parent to leukaemogenic environmental hazards, particularly ionizing radiation. Mathematical modelling of leukaemogenesis suggests that any such patient would be especially prone to multiple independent leukaemogenic events leading to multiclonality in terms of cell of origin (analogous to bilaterality in familial retinoblastoma). To test this hypothesis we have carried out a search for multiclonal leukaemogenesis in infant and childhood acute lymphoblastic leukaemia (ALL). We used a polymerase chain reaction-based analysis of the X-linked monoamine oxidase A (MAOA) gene locus to study the clonality of marrow samples obtained from female paediatric ALL patients at the time of disease presentation. We obtained presentation samples from 102 patients of whom 72 were found to be informative at the MAOA locus. These included 20 infant leukaemias (< 1 year at diagnosis). Sixty-six samples were found to be unequivocally monoclonal while the remaining six could not, with certainty, be assigned a clonal origin. We also obtained bone marrow aspirates at first relapse as well as at presentation from eight patients. In each case the same pattern of X-linked allelic inactivation was observed at both time points of the course of the disease. No evidence was found for leukaemic multiclonality in any age group at presentation or for leukaemic 'clone-switching' in relapse. These findings suggest that both infant and childhood ALL is of single-cell origin and implies that leukaemic predisposition resulting from germ cell mutation is unlikely to have a major role in their pathogenesis.

Molecular mechanisms of ageing and related diseases

“…Many age-related diseases stem from a single cell or a group of cells with age-related injures. [1][2][3][4][5][6][7] The ageing cells initiate inflammation by releasing detrimental substances to inflame surrounding tissues, which cause further ageing, known as the senescence-associated secretary phenotype (SASP). [8][9][10][11][12][13][14] Senescence occurs as a degenerative phenotype, with the term most often used in studies of cellular senescence.…”

“…Ageing is a risk factor of many diseases under both physiological and pathophysiological conditions. Many age‐related diseases stem from a single cell or a group of cells with age‐related injures . The ageing cells initiate inflammation by releasing detrimental substances to inflame surrounding tissues, which cause further ageing, known as the senescence‐associated secretary phenotype (SASP) .…”