Dynamics of competing heterogeneous clones in blood cancers explains multiple observations - a mathematical modeling approach

Katrine O. Bangsgaard; Morten Andersen; Vibe Skov; Lasse Kjær; Hans C. Hasselbalch; Johnny T. Ottesen; Katrine O. Bangsgaard; Morten Andersen; Vibe Skov; Lasse Kjær; Hans C. Hasselbalch; Johnny T. Ottesen

doi:10.3934/mbe.2020389

Mathematical Biosciences and Engineering

2020, Volume 17, Issue 6: 7645-7670. doi: 10.3934/mbe.2020389

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Dynamics of competing heterogeneous clones in blood cancers explains multiple observations - a mathematical modeling approach

1.
IMFUFA, Department of Science and Environment, Roskilde University, Roskildevej 1, DK 4000, Denmark
2.
Department of Hematology, Zealand University Hospital, Sygehusvej 10, DK 4000, Denmark

Received: 29 June 2020 Accepted: 11 October 2020 Published: 04 November 2020

Heterogeneity of stem cell clones provide a key ingredient in altered hematopoiesis and is of main interest in the study of predisease states as well as in the development of blood cancers such as chronic myeloid leukemia (CML) and the Philadelphia-negative myeloprofilerative neoplasms (MPNs). A mathematical model based on biological mechanisms and basic cell descriptors such as proliferation rates and apoptosis rates is suggested, connecting stem cell dynamics with mature blood cells and immune mediated feedback. The flexible approach allows for arbitrary numbers of mutated stem cell clones with perturbed properties. In particular, the stem cell niche provides a competition between wild type and mutated stem cells. Hence, the stem cell niche can mediate suppression of the wild type clones and up-regulation of one or more malignant clones. The model is parameterized using clinical data to show typical disease progression in several blood cancers and the hematological and molecular response to treatment. Intriguingly, occasional oscillatory cell counts observed during treatment of CML and MPNs can be explained by heterogeneous stem cell clone dynamics. Thus, the vital heterogeneous stem cell dynamics may be inferred from mathematical modeling in synergy with clinical data to elucidate hematopoiesis, blood cancers and the outcome of interventions.
- hematopoiesis,
- blood cancer,
- mathematical modeling,
- stem cell dynamics,
- competition dynamics,
- inflammation
Citation: Katrine O. Bangsgaard, Morten Andersen, Vibe Skov, Lasse Kjær, Hans C. Hasselbalch, Johnny T. Ottesen. Dynamics of competing heterogeneous clones in blood cancers explains multiple observations - a mathematical modeling approach[J]. Mathematical Biosciences and Engineering, 2020, 17(6): 7645-7670. doi: 10.3934/mbe.2020389

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Abstract

Heterogeneity of stem cell clones provide a key ingredient in altered hematopoiesis and is of main interest in the study of predisease states as well as in the development of blood cancers such as chronic myeloid leukemia (CML) and the Philadelphia-negative myeloprofilerative neoplasms (MPNs). A mathematical model based on biological mechanisms and basic cell descriptors such as proliferation rates and apoptosis rates is suggested, connecting stem cell dynamics with mature blood cells and immune mediated feedback. The flexible approach allows for arbitrary numbers of mutated stem cell clones with perturbed properties. In particular, the stem cell niche provides a competition between wild type and mutated stem cells. Hence, the stem cell niche can mediate suppression of the wild type clones and up-regulation of one or more malignant clones. The model is parameterized using clinical data to show typical disease progression in several blood cancers and the hematological and molecular response to treatment. Intriguingly, occasional oscillatory cell counts observed during treatment of CML and MPNs can be explained by heterogeneous stem cell clone dynamics. Thus, the vital heterogeneous stem cell dynamics may be inferred from mathematical modeling in synergy with clinical data to elucidate hematopoiesis, blood cancers and the outcome of interventions.

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