Neutral evolution in paroxysmal nocturnal hemoglobinuria

Dingli, David; Luzzatto, Lucio; Pacheco, Jorge M.

doi:10.1073/pnas.0802749105

Cited by 48 publications

(57 citation statements)

References 54 publications

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“…32,33 However, other hypotheses such as secondary mutations, 34 resistance to apoptosis 35.36 or even neutral evolution have been proposed. 37 Regardless of the mechanism, our data suggest that PIG-A mutations arise from a multipotent HSC in both PNH and AA. We were unable to detect GPI-anchor deficient T lymphocytes or CFC using proaerolysin selective enrichment in any of the 3 patients (A13, A14, and A15) who had no detectable GPI-anchor deficient granulocytes (Figure 2).…”

Section: Discussionmentioning

confidence: 93%

The small population of PIG-A mutant cells in myelodysplastic syndromes do not arise from multipotent hematopoietic stem cells

Pu¹,

Hu²,

Mukhina³

et al. 2012

Haematologica

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Section: Discussionmentioning

confidence: 93%

The small population of PIG-A mutant cells in myelodysplastic syndromes do not arise from multipotent hematopoietic stem cells

Pu¹,

Hu²,

Mukhina³

et al. 2012

Haematologica

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“…The nature of the Moran process leads to the typical scenarios associated with stochastic evolutionary dynamics: expansion, extinction and latency of the LSC clone. 18,28,30 The impact of these stochastic effects 14,18 on clone size at the level of the stem cell compartment plays a crucial role and is discussed below.…”

Section: Stochastic Dynamics Of Leukemic Stem Cellsmentioning

confidence: 99%

Tyrosine kinase inhibitor therapy can cure chronic myeloid leukemia without hitting leukemic stem cells

Lenaerts¹,

Pacheco²,

Traulsen³

et al. 2009

Haematologica

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BackgroundTyrosine kinase inhibitors, such as imatinib, are not considered curative for chronic myeloid leukemia -regardless of the significant reduction of disease burden during treatment -since they do not affect the leukemic stem cells. However, the stochastic nature of hematopoiesis and recent clinical observations suggest that this view must be revisited. Design and MethodsWe studied the natural history of a large cohort of virtual patients with chronic myeloid leukemia under tyrosine kinase inhibitor therapy using a computational model of hematopoiesis and chronic myeloid leukemia that takes into account stochastic dynamics within the hematopoietic stem and early progenitor cell pool. ResultsWe found that in the overwhelming majority of patients the leukemic stem cell population undergoes extinction before disease diagnosis. Hence leukemic progenitors, susceptible to tyrosine kinase inhibitor attack, are the natural target for chronic myeloid leukemia treatment. Response dynamics predicted by the model closely match data from clinical trials. We further predicted that early diagnosis together with administration of tyrosine kinase inhibitor opens the path to eradication of chronic myeloid leukemia, leading to the wash out of the aberrant progenitor cells, ameliorating the patient's condition while lowering the risk of blast transformation and drug resistance. ConclusionsTyrosine kinase inhibitor therapy can cure chronic myeloid leukemia, although it may have to be prolonged. The depth of response increases with time in the vast majority of patients. These results illustrate the importance of stochastic effects on the dynamics of acquired hematopoietic stem cell disorders and have direct relevance for other hematopoietic stem cell-derived diseases.Key words: chronic myeloid leukemia, tyrosine kinase inhibitors, cure, stochastic dynamics. Citation: Lenaerts T, Pacheco JM, Traulsen

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“…In patients with concomitant PNH and MDS, other studies have found trisomy 8 in the fraction of GPI-deficient cells, suggesting that the PIGA mutation affected the stem cell first, and chromosomal aberrations evolved within a subclone thereafter [5,33,34]. Recently, it was shown that a stochastic model of clonal stem cell evolution could capture some of the features of PNH [35]. However, the exact mechanism of clonal dominance remains unclear in most PNH patients, and secondary clonal events seem to be rare, in line with recent findings by whole exome sequencing of PNH affected cells [19].…”

Section: Discussionmentioning

confidence: 99%

Chromosomal Aberrations and HMGA2 Expression in Paroxysmal Nocturnal Hemoglobinuria

Sellmann¹,

Klein-Hitpaß²,

Gesk³

et al. 2016

Journal of Hematology and Blood Disorders

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Neutral evolution in paroxysmal nocturnal hemoglobinuria

Cited by 48 publications

References 54 publications

The small population of PIG-A mutant cells in myelodysplastic syndromes do not arise from multipotent hematopoietic stem cells

The small population of PIG-A mutant cells in myelodysplastic syndromes do not arise from multipotent hematopoietic stem cells

Tyrosine kinase inhibitor therapy can cure chronic myeloid leukemia without hitting leukemic stem cells

Chromosomal Aberrations and HMGA2 Expression in Paroxysmal Nocturnal Hemoglobinuria

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