Biology subjects

Baldow, C.

Publications and source records attributed to Baldow, C..

3 recordsLinked to original sources

bioRxiv2021

Clonal reconstruction from co-occurrence of vector integration sites allows accurate quantification of expanding clones in vivo

High transduction rates of viral vectors in gene therapies (GT) and experimental hematopoiesis ensure a high frequency of gene delivery, although multiple integration events can occur in the same cell. Therefore, tracing of integration sites (IS) leads to misquantification of the true clonal spectrum and limits safety considerations in GT. Hence, we use correlations between repeated measurements of IS abundances to estimate their mutual similarity and identify clusters of co-occurring IS, for which we assume a clonal origin. We evaluate the performance, robustness and specificity of our methodology using clonal simulations. The reconstruction methods, implemented and provided as an R-package, are further applied to experimental clonal mixes and to a preclinical model of hematopoietic GT. Our results demonstrate that clonal reconstruction from IS data allows to overcome systematic biases in the clonal quantification as an essential prerequisite for the assessment of safety and long-term efficacy of GT involving integrative vectors.

cancer biology↗

bioRxiv2020

Mathematical modelling of megakaryopoiesis in Mpl-deficient and continuously thrombopoietin-stimulated mice points to an unknown control mechanism

Thrombopoietin (TPO) is the ligand of the Mpl receptor and the key regulator of megakaryopoiesis and platelet production. A loss or gain of the TPO-receptor function affects haematopoiesis and results in severe diseases in humans. Appropriate mouse strains are available to mimic both myeloproliferative neoplasm (MPN) and congenital amegakaryocytic thrombocytopenia (CAMT) resulting from TPO overexpression or knockout of TPO receptor Mpl on megakaryocytes and platelets, respectively. However, at a quantitative level it is not understood, how the known regulations can establish the impaired but stable disease phenotypes. Starting out from an established mathematical model for megakaryopoiesis, we aim to adapt it to both the healthy situation and to distinct diseased phenotypes mimicking MPN. We thereby identify, that some of the model parameters are invariant with respect to the mouse strain while others have to be estimated in a strain-dependent manner. A systematic process of parameter identification provides strong evidence that the well-known excess production of megakaryocytes and early progenitors in MPN is either directly contingent on Mpl expression of platelets and megakaryocytes or, alternatively, that the knockout of Mpl is not as precisely restricted to megakaryocytes and platelets but may also effect their progenitors. In conclusion, our analysis hints towards an opaque control mechanism rendering megakaryopoiesis at a yet unknown level, and awaiting further experimental evaluation.

systems biology↗

bioRxiv2019

Inferring immunological control mechanisms from TKI dose alterations in CML patients

Recent clinical findings in chronic myeloid leukemia (CML) patients suggest that the risk of molecular recurrence after stopping tyrosine kinase inhibitors (TKI) treatment substantially depend on an individual, leukemia-specific immune response. However, it is still not possible to prospectively identify patients that will most likely remain in a long-term treatment free remission (TFR). Here, we use a mathematical model for CML, which explicitly includes an anti-leukemic (presumably immunological) effect and apply it to a set of patients (n=60) for whom BCR-ABL/ABL time courses had been quantified before and after TKI stop. We demonstrate that such a feedback control is conceptually necessary to explain long-term remission as observed in about half of the patients. Based on simulation results we classify the patient data sets into three different groups according to their predicted immune system configuration. While one class of patients requires a complete CML eradication to achieve TFR, other patients are able to control the leukemia after treatment cessation. Among them, we identified a third class of patients, which only maintains TFR if an optimal balance between leukemia abundance and immunological activation is achieved before treatment cessation. Further, we demonstrate that the immune response classification of the patients cannot be obtained solely from BCR-ABL measurements before treatment cessation. However, our results strongly suggest that changes in the BCR-ABL dynamics arising after system perturbations, such as TKI dose reduction, holds the information to predict the individual outcome after treatment cessation.

systems biology↗