Global Behavior of a Discrete Survival Model with Several Delays

The difference equation yn+1−yn=−αyn+∑j=1mβje−γjyn−kj is studied and some sufficient conditions which guarantee that all solutions of the equation are oscillatory, or that the positive equilibrium of the equation is globally asymptotically stable, are obtained

Dynamics of erythroid progenitors and erythroleukemia

International audienceThe paper is devoted to mathematical modelling of erythropoiesis, production of red blood cells in the bone marrow. We discuss intra-cellular regulatory networks which determine self-renewal and differentiation of erythroid progenitors. In the case of excessive self-renewal, immature cells can fill the bone marrow resulting in the development of leukemia. We introduce a parameter characterizing the strength of mutation. Depending on its value, leukemia will or will not develop. The simplest model of treatment of acute myeloid leukemia with chemotherapy allows us to determine the conditions of successful treatment or of its failure. We show that insufficient treatment can worsen the situation. In some cases curing may not be possible even without resistance to treatment. Modelling presented in this work is based on ordinary differential equations, reaction-diffusion systems and individual based approach

Équations différentielles à retard et leur application en hématopoïèse, avec étude du cas de la neutropénie cyclique

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal

The role of YTHDF1 and YTHDF3 in normal and malignant haematopoiesis

Epitranscriptomics is the field of research that investigates the role of post-transcriptional mRNA modifications and the function of their regulating machinery in a wide range of biological contexts. The best characterised modification is N6-Methyladenosine (m6A), placed by the writer complex METTL3-METTL14, removed by ALKBH5 and FTO and recognised by reader molecules including the YTHDF family of proteins. Within haematopoiesis and leukaemia research, the reader YTHDF2, responsible for the decay of mRNA molecules labelled with m6A, has recently emerged as a promising candidate for the treatment of Acute Myeloid Leukaemia (AML) whose inhibition does not derail haematopoiesis in the short term. However, its application in the clinic is impaired by lack of knowledge about the function of related proteins YTHDF1 and YTHDF3, as well as potential mutual interactions. Here, I show that YTHDF1 and YTHDF3 are dispensable for steady-state haematopoiesis and are not required to maintain haematopoietic stem cell (HSC) reconstitution capacity following primary and secondary transplantation. Moreover, deletion of Ythdf1 prolongs the activation state of HSCs following haematopoietic injury by delaying the resolution of inflammatory states, accelerating their recovery following chemotherapy in a time-limited response. To explain its expression in the system, I uncover a role in long-term control of HSC expansion during ageing or upon multiple stimulation to preserve their differentiation capacity and avoid exhaustion. At the same time, inhibition of YTHDF1 impairs AML maintenance by promoting the differentiation of leukemic stem cells, showing a synergistic effect with YTHDF2 inhibition likely due to the contextual activation of pro-apoptotic signalling pathways downstream of TNFR2. These results highlight the potential benefits of YTHDF1 inhibition for patients undergoing chemotherapy and establish a base for the use of broad spectrum YTHDF family inhibitors for the treatment of AML, while easing concerns regarding their short-term toxicity

Towards Executable Biology

Heringa, J. [Promotor]Fokkink, W.J. [Promotor]Feenstra, K.A. [Copromotor

The epigenetic and transcriptional consequences of aberrant FoxC1 expression in acute myeloid leukaemia

FOXC1 encodes a mesenchymal transcription factor that is not normally expressed in haematopoietic cells. However, recent studies from this and another laboratory demonstrated that FOXC1 is inappropriately de-repressed in Acute Myeloid Leukaemia (AML). Through epigenomic profiling of primary AML samples, we showed that FOXC1 was specifically upregulated in the aggressive FLT3-ITD subtype of AMLs, in parallel with the activation of FOX:E-box composite cis-regulatory elements. Furthermore, complementary studies from the Somervaille laboratory demonstrated that FoxC1 expression in AML was leukaemogenic by establishment of a monocyte differentiation block and enhancement of clonogenic potential. Collectively, these data indicated that FoxC1 plays a critical role in leukaemogenesis, but the target genes and mechanisms by which this occurred were not known. To address this, we performed an integrative genome-wide analysis of FoxC1 binding, chromatin accessibility and gene expression in primary AML samples, in vivo models and cell lines. These studies revealed that FoxC1 acts to block normal myeloid differentiation by contributing to the widespread repression of differentiation-specific target genes. Critically, we identify Meis2, a proto-oncogene which collaborates with Hoxa9, as a putative direct target of FoxC1, providing compelling indications of a potential FoxC1-dependent oncogenic mechanism

Emergence of the erythroid lineage from multipotent hematopoiesis [preprint]

Red cell formation begins with the hematopoietic stem cell, but the manner by which it gives rise to erythroid progenitors, and their subsequent developmental path, remain unclear. Here we combined single-cell transcriptomics of murine hematopoietic tissues with fate potential assays to infer a continuous yet hierarchical structure for the hematopoietic network. We define the erythroid differentiation trajectory as it emerges from multipotency and diverges from 6 other blood lineages. With the aid of a new flow-cytometric sorting strategy, we validated predicted cell fate potentials at the single cell level, revealing a coupling between erythroid and basophil/mast cell fates. We uncovered novel growth factor receptor regulators of the erythroid trajectory, including the proinflammatory IL- 17RA, found to be a strong erythroid stimulator; and identified a global hematopoietic response to stress erythropoiesis. We further identified transcriptional and high-purity FACS gates for the complete isolation of all classically-defined erythroid burst-forming (BFU-e) and colony-forming progenitors (CFU-e), finding that they express a dedicated transcriptional program, distinct from that of terminally-differentiating erythroblasts. Intriguingly, profound remodeling of the cell cycle is intimately entwined with CFU-e developmental progression and with a sharp transcriptional switch that extinguishes the CFU-e stage and activates terminal differentiation. Underlying these results, our work showcases the utility of theoretic approaches linking transcriptomic data to predictive fate models, providing key insights into lineage development in vivo

Effects of high -dose chemotherapy on the bone marrow microenvironment

The bone marrow microenvironment composed in part of stromal cells provides the niche in which normal hematopoiesis occurs. Hematopoiesis generates cellular components of the immune system and blood through proliferation and differentiation of multipotent hematopoietic stem cells (HSC). In preparation for bone marrow transplantation, radiation or chemotherapy treatment temporarily disrupts the balance of hematopoiesis as many HSC and progenitor cells are destroyed. Following treatment cessation, transplanted HSC and progenitor cells migrate, or home , back to the bone marrow microenvironment and initiate productive hematopoiesis. While the mechanism of bone marrow homing is not completely understood, several soluble factors and adhesion molecules are known to have specific roles in the process. The chemokine stromal derived factor-1 (SDF-1) and the adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) are critical in mediating HSC chemotaxis and adhesion, respectively. In addition, both molecules have been demonstrated to be critical for maintenance of productive hematopoiesis.;We previously demonstrated and characterized stromal cell VCAM-1 protein down-regulation following in vitro exposure to the topoisomerase II inhibitor etoposide (VP-16). VP-16-induced VCAM-1 down-regulation is associated with an impairment of stromal cell layers to support early lymphoid and myeloid cell proliferation. More recently, we evaluated stromal cell SDF-1 protein production following exposure to several chemotherapeutic drugs, and we found that bone marrow stromal cell SDF-1 protein secretion is also disrupted following VP-16 or doxorubicin exposure. SDF-1 protein reductions correlated with a reduced capacity of B-cell progenitor lines to migrate toward chemotherapy-treated stromal cell layers. Finally, we have generated and characterized murine stromal cell lines that constitutively express human VCAM-1 protein. Human VCAM-1 expression is maintained following exposure to VP-16 and overall elevation of VCAM-1 protein offset diminished viabilities in B cell progenitors following removal of exogenous IL-7.;This research will contribute to better understanding mechanistic models that address the hypothesis that aggressive chemotherapy disrupts immune system reconstitution through bone marrow microenvironment damage and disruption of molecules that regulate homing. Ultimately, this work may improve our understanding of delayed immune system recovery following aggressive chemotherapy and lead to enhanced cancer treatment strategies