Cyclic neutropenia in mammals

Pacheco, Jorge M.; Traulsen, Arne; Antal, Tibor; Dingli, David

doi:10.1002/ajh.21295

Cited by 15 publications

(13 citation statements)

References 20 publications

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“…The leukemic stem cell in APL may arise in a CFU-GM cell (13, 21), and therefore l = 15 was chosen as the founding compartment of APL in our hierarchical model, based on our prior results (1, 39). We estimated that the minimum time between the onset of the first leukemic stem cell and disease was 872 days (13, 19, 20), where disease was defined as a reduction in bone marrow output to ∼20% of normal, leading to cytopenias that are typical for this leukemia. At the same time, the bone marrow compartments will be expanded and the marrow appears hypercellular.…”

Section: Resultsmentioning

confidence: 99%

“…For our parameters, we obtain 4 × 10 7 leukemic stem cells at the time of diagnosis in compartment 15 (CFU-GM), where the mutation originates (19,20). Under ATRA therapy, the number of leukemic stem cells decreases exponentially such that…”

Section: Resultsmentioning

confidence: 99%

“…Using data from Guibal et al (13), we inferred that the minimum time for diagnosis in mice is ∼ 120 days. Using our previously described allometric scaling relationship (19, 20) comparing timescales between mice and men,

\frac{T_{italicmi}}{T_{italichu}} = {(\frac{M_{italicmi}}{M_{italichu}})}^{1 / 4}

where T and M refer to the time to diagnosis and the species specific adult mass respectively, we could determine that the minimum time from the appearance of the first leukemic stem cell in humans to diagnosis is > 872 days. An animal model of APL suggests that the disease may originate in a CFU-GM cell (13), which in our model would reside in compartments 13 - 15.…”

Section: Quick Guide To Equations and Assumptionsmentioning

confidence: 99%

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Dynamics of Leukemia Stem-like Cell Extinction in Acute Promyelocytic Leukemia

et al. 2014

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Many tumors are believed to be maintained by a small number of cancer stem-like cells where cure is thought to require eradication of this cell population. In this study, we investigated the dynamics of acute promyelocytic leukemia (APL) before and during therapy with regard to disease initiation, progression and therapeutic response. This investigation employed a mathematical model of hematopoiesis and a dataset derived from the North American Intergroup Study INT0129. The known phenotypic constraints of APL could be explained by a combination of differentiation blockade of PML-RARα positive cells and suppression of normal hematopoiesis. ATRA neutralizes the differentiation block and decreases the proliferation rate of leukemic stem cells in vivo. Prolonged ATRA treatment after chemotherapy can cure APL patients by eliminating the stem-like cell population over the course of approximately one year. To our knowledge, this study offers the first estimate of the average duration of therapy that is required to eliminate stem-like cancer cells from a human tumor, with the potential for the refinement of treatment strategies to better manage human malignancy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

\frac{T_{italicmi}}{T_{italichu}} = {(\frac{M_{italicmi}}{M_{italichu}})}^{1 / 4}

Section: Quick Guide To Equations and Assumptionsmentioning

confidence: 99%

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Dynamics of Leukemia Stem-like Cell Extinction in Acute Promyelocytic Leukemia

et al. 2014

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“…Theoretical models of varying levels of mathematical complexity have been proposed 104, 105 . A common element to some models involves disturbance of a feedback loop 106 .…”

Section: Hypotheses For Pathogenicity: General Considerationsmentioning

confidence: 99%

ELANE Mutations in Cyclic and Severe Congenital Neutropenia

Horwitz

Corey

Grimes

et al. 2013

Hematology/Oncology Clinics of North America

108

103

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There are two main forms of hereditary neutropenia: cyclic and severe congenital neutropenia (SCN). Cyclic neutropenia is an autosomal dominant disorder in which neutrophil counts fluctuate between nearly normal levels and close to zero with 21-day periodicity. In contrast, SCN, also known as Kostmann syndrome, consists of chronic and profound neutropenia, with a characteristic promyelocytic maturation arrest in the bone marrow. Unlike cyclic neutropenia, SCN displays frequent acquisition of somatic mutations in the gene, CSF3R, encoding the Granulocyte Colony-Stimulating Factor Receptor (G-CSFR), and a strong predisposition to developing myelodysplasia (MDS) and/or acute myeloid leukemia (AML). Cyclic neutropenia is caused by heterozygous mutations in the gene, ELANE (formerly known as ELA2), encoding the neutrophil granule serine protease, neutrophil elastase. SCN is genetically heterogeneous, but it is most frequently associated with ELANE mutations. While some of the different missense mutations in ELANE exhibit phenotype-genotype correlation, the same mutations are sometimes found in patients with either form of inherited neutropenia. The mutations lead to production of a mutant polypeptide, but no common biochemical abnormality, including effects on proteolysis, has been identified. Two non-mutually exclusive theories have been advanced to explain how the mutations might produce neutropenia. The mislocalization hypothesis states that mutations within neutrophil elastase or involving other proteins responsible for its intracellular trafficking cause neutrophil elastase to accumulate in inappropriate subcellular compartments. The misfolding hypothesis proposes that mutations prevent the protein from properly folding, thereby inducing the stress response pathway within the endoplasmic reticulum (ER). We discuss how the mutations themselves provide clues into pathogenesis, describe supporting and contradictory observations for both theories, and highlight outstanding questions relating to pathophysiology of neutropenia.

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“…However, from a quantitative viewpoint our collective knowledge is still lacking, in no small part due to the fact that in vivo studies of the bone marrow cell dynamics present numerous challenges. Still, in the past decades a handful of mathematical models of hematopoiesis have been developed [8][9][10][11][12][13][14][15][16][17][18][19] leading to important insights on several of its properties.…”

Section: Introductionmentioning

confidence: 99%

Multistage feedback driven compartmental dynamics of hematopoiesis

Père

Lenaerts

Pacheco

et al. 2020

Preprint

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Human hematopoiesis is surprisingly resilient to disruptions, providing suitable responses to severe bleeding, long lasting immune activation, and even bone marrow transplants. Still, many blood disorders exist which push the system past its natural plasticity, resulting in abnormalities in the circulating blood. While proper treatment of such diseases can benefit from understanding the underlying cell dynamics, these are non-trivial to predict due to the hematopoietic system’s hierarchical nature and complex feedback networks. To characterize the dynamics following different types of perturbations we investigate a model representing hematopoiesis as a sequence of compartments covering all maturation stages – from stem to mature cells – where feedback regulates cell production to ongoing necessities. We find that a stable response to perturbations requires the simultaneous adaptation of cell differentiation and self-renewal rates, and show that under conditions of continuous disruption – as found in chronic hemolytic states – compartment cell numbers evolve to novel stable states.

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Cyclic neutropenia in mammals

Cited by 15 publications

References 20 publications

Dynamics of Leukemia Stem-like Cell Extinction in Acute Promyelocytic Leukemia

Dynamics of Leukemia Stem-like Cell Extinction in Acute Promyelocytic Leukemia

ELANE Mutations in Cyclic and Severe Congenital Neutropenia

Multistage feedback driven compartmental dynamics of hematopoiesis

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