Logical modelling of myelofibrotic microenvironment predicts dysregulated progenitor stem cell crosstalk

Taxon: Mammal | Stem cells | Haematopoietic stem cells | Mesenchymal stem cells
Process: Cell fate decision
Submitter: Pedro Monteiro

Supporting paper: Desterke, Christophe and Martinaud, Christophe and Ruzehaji, Nadira and Le Bousse-Kerdilès, Marie-Caroline (2015). Inflammation as a Keystone of Bone Marrow Stroma Alterations in Primary Myelofibrosis. Mediators of Inflammation. 10.1155/2015/415024

Model file(s)	Description(s)
HSC_MSC_MK.zginml	GINsim file

Summary:
Idiopathic primary myelofibrosis is an age-related clonal neoplastic disorder of haematopoiesis characterised by a myeloproliferation and myelofibrosis. Recent evidence suggests that disease onset results from an altered bone marrow microenvironment, leading to disrupted crosstalk between progenitor haematopoietic and mesenchymal stem cells populations. 90% of myelofibrosis cases exhibit ectopic mutations of JAK2, CALR and, or MPL genes which all converge on the activation of JAK and STAT signaling pathways. Treatments aiming to target STAT overactivity have been developed; however, disease management is conducted at advanced stages of the disease and treatments are not effective. A computational description of how altered microenvironments can lead to dysregulated crosstalk between haematopoietic and mesenchymal stem cells populations following STAT activation would increase our knowledge of disease pathology and influence future treatment protocols. To meet this aim, we have constructed a logical model that accounts for the myelofibrotic microenvironment following TPO and lTLR signalling, integrated with JAK-STAT signalling. The model primarily aims to provide a mechanistic understanding of the dysregulated crosstalk between progenitor HSC’s, MSC’s and the microenvironment to predict the onset of PMF with, and without the JAK activation. Wildtype simulations result in 4 cyclic attractors being obtained, all depending on combination of inputs being modelled. The model predicted that presence of TPO and lTLR signalling are both required to facilitate disease onset for wildtype simulations. For simulations involving JAK knock-in mutated scenarios, the model resulted in 4 fixed point attractors, with the presence of lTLR alone being sufficient to drive disease progression.