A two-stage model for childhood acute lymphoblastic leukemia: Application to hereditary and nonhereditary leukemogenesis

Wheldon, Elizabeth G.; Lindsay, K. A.; Wheldon, T. E.; Mao, Jian‐Hua

doi:10.1016/s0025-5564(96)00136-8

Cited by 4 publications

(5 citation statements)

References 17 publications

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“…Despite the restrictive assumptions of the calculation, it seems unlikely that we would have failed to observe 'clone-switching' in any of eight cases, if multiclonal leukaemogenesis were usually occurring. A further area of uncertainty concerns the mathematical model which predicts multiclonality were a germ cell mutation to be inherited (Wheldon et al, 1997). We have previously mentioned that more than two leukaemogenic mutations may in fact be required, although this does not seem plausible in the case of infant leukaemia.…”

Section: Discussionmentioning

confidence: 99%

“…Multiclonality following a predisposing germ cell mutation is easily understood as resulting from the large number of somatic cells which need only acquire one further mutation to experience malignant transformation. The predicted number of leukaemic clones (> 10) is greater than the number of independently occurring tumours (about 3) estimated for familial retinoblastoma (Knudson, 1971) because the higher incidence of ALL requires higher mutation rates to be assigned to the two-mutation model (Wheldon et al, 1997). As in Knudson's model, a small proportion of genetically predisposed leukaemias may present (by chance) as a single clone: however, the present modelling studies (Wheldon et al, 1997) suggest that the fraction of heritably predisposed ALL patients who would present in this way is close to zero.…”

mentioning

confidence: 86%

“…The predicted number of leukaemic clones (> 10) is greater than the number of independently occurring tumours (about 3) estimated for familial retinoblastoma (Knudson, 1971) because the higher incidence of ALL requires higher mutation rates to be assigned to the two-mutation model (Wheldon et al, 1997). As in Knudson's model, a small proportion of genetically predisposed leukaemias may present (by chance) as a single clone: however, the present modelling studies (Wheldon et al, 1997) suggest that the fraction of heritably predisposed ALL patients who would present in this way is close to zero. Therefore, we expect multiclonality in almost all presenting ALL cases who have inherited a first mutation (provided of course that the two-mutation model is valid).…”

mentioning

confidence: 86%

“…We have mathematically modelled 'two hit' leukaemogenesis with both mutations occurring somatically, or with one transmissible via the germ line. With parameters chosen to simulate the observed age-incidence of ALL, these studies predict that inheritance of the first mutation would cause multiple independent leukaemogenic transformation in the haematopoietic cells of each individual, typically resulting in ten or more independently arising leukaemic clones by time of diagnosis (Wheldon et al, 1997). Multiclonality following a predisposing germ cell mutation is easily understood as resulting from the large number of somatic cells which need only acquire one further mutation to experience malignant transformation.…”

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confidence: 99%

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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

et al. 1999

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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.

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Section: Discussionmentioning

confidence: 99%

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confidence: 86%

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confidence: 86%

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confidence: 99%

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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

et al. 1999

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“…The stochastic model claims that all cancer cells can reproduce phenotypically heterogeneous cell types in new tumors. [13] However, this model cannot explain why cancer is highly heterogeneous. The cancer stem cell hypothesis may resolve the issue.…”

Section: Introductionmentioning

confidence: 99%

Cancer stem cell: A rogue responsible for tumor development and metastasis

Kapoor¹,

Kumar²

2014

Indian J Cancer

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Cancer stem cells are a small population of cells in a tumor. They have the ability to self-renew and maintain the tumor. The most apt and accepted hypothesis for tumor development is Cancer Stem Cells. This review focuses on this concept of cancer stem cells, serving their purpose and leading to the development of tumor. There are many cell biomarkers which have been described for the identification and characterization of cancer stem cells. The most prominent of the cellular markers for the detection of cancer stem cells; CD133, CD44, ALDH-1 along with some others have been discussed in detail in this review.

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Using adaptive model predictive control to customize maintenance therapy chemotherapeutic dosing for childhood acute lymphoblastic leukemia

Noble

Sherer

Hannemann

et al. 2010

Journal of Theoretical Biology

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A two-stage model for childhood acute lymphoblastic leukemia: Application to hereditary and nonhereditary leukemogenesis

Cited by 4 publications

References 17 publications

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

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

Cancer stem cell: A rogue responsible for tumor development and metastasis

Using adaptive model predictive control to customize maintenance therapy chemotherapeutic dosing for childhood acute lymphoblastic leukemia

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