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Bone marrow infiltration by multiple myeloma causes anemia by reversible disruption of erythropoiesis

Anass Bouchnita 1, 2 Nathalie Eymard 3 Tamara K Moyo 4 Mark J Koury 4 Vitaly Volpert 4, 1 
1 MMCS - Modélisation mathématique, calcul scientifique
ICJ - Institut Camille Jordan [Villeurbanne]
2 Evaluation et modélisation des effets thérapeutiques
Département biostatistiques et modélisation pour la santé et l'environnement [LBBE]
4 DRACULA - Multi-scale modelling of cell dynamics : application to hematopoiesis
CGPhiMC - Centre de génétique et de physiologie moléculaire et cellulaire, Inria Grenoble - Rhône-Alpes, ICJ - Institut Camille Jordan [Villeurbanne]
Abstract : Multiple myeloma (MM) infiltrates bone marrow and causes anemia by disrupting erythropoiesis, but the effects of marrow infiltration on anemia are difficult to quantify. Marrow biopsies of newly diagnosed MM patients were analyzed before and after four 28-day cycles of nonerythrotoxic remission induction chemotherapy. Complete blood cell counts and serum paraprotein concentrations were measured at diagnosis and before each chemotherapy cycle. At diagnosis, marrow area infiltrated by myeloma correlated negatively with hemoglobin, erythrocytes, and marrow erythroid cells. After successful chemotherapy, patients with less than 30% myeloma infiltration at diagnosis had no change in these parameters, whereas patients with more than 30% myeloma infiltration at diagnosis increased all three parameters. Clinical data were used to develop mathematical models of the effects of myeloma infiltration on the marrow niches of terminal erythropoiesis, the erythroblastic islands (EBIs). A hybrid discrete-continuous model of erythropoiesis based on EBI structure/function was extended to sections of marrow containing multiple EBIs. In the model, myeloma cells can kill erythroid cells by physically destroying EBIs and by producing proapoptotic cytokines. Following chemotherapy, changes in serum paraproteins as measures of myeloma cells and changes in erythrocyte numbers as measures of marrow erythroid cells allowed modeling of myeloma cell death and erythroid cell recovery, respectively. Simulations of marrow infiltration by myeloma and treatment with nonerythrotoxic chemotherapy demonstrate that myeloma-mediated destruction and subsequent reestablishment of EBIs and expansion of erythroid cell populations in EBIs following chemotherapy provide explanations for anemia development and its therapy-mediated recovery in MM patients.
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Submitted on : Monday, November 14, 2016 - 11:07:09 AM
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Anass Bouchnita, Nathalie Eymard, Tamara K Moyo, Mark J Koury, Vitaly Volpert. Bone marrow infiltration by multiple myeloma causes anemia by reversible disruption of erythropoiesis. American Journal of Hematology, Wiley, 2016, 91 (4), pp.371 - 378. ⟨10.1002/ajh.24291⟩. ⟨hal-01395624⟩



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