The granulocyte is absolutely essential for host defense and survival. Its pathophysiological importance is apparent in severe congenital neutropenia (SCN). Life-threatening infections in children with SCN can be avoided through the use of recombinant granulocyte colony-stimulating factor (GCSF), which increases the number of granulocytes. However, SCN often transforms into myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). A great unresolved clinical question is: do chronic, pharmacologic doses of GCSF contribute to this transformation. Two major sets of human clinical and experimental data strongly suggest such a linkage. First, a number of epidemiological clinical trials have demonstrated a strong association between exposure to GCSF and MDS/AML. Second, mutations in the distal domain of the GCSF Receptor (GCSFR) have been isolated from 70% of patients with SCN who developed MDS/AML. Most recently, clonal evolution over ~20 years was documented in a patient with SCN who developed MDS/AML. What is very striking is that five different mutations arose in the GCSFR gene, one persisted into the AML clone but others became extinct during the course. We hypothesize that clonal evolution of an SCN sick stem cell involves perturbations in proximal and distal signaling networks triggered by a mutant GCSFR. Transition from SCN?MDS?AML most likely also depends on chance, hence the need for a stochastic model. To address these hypotheses through computational modeling and experimental validation, we propose the following specific aims:
Aim 1) Develop and evaluate a network model to account for the dynamics of normal and aberrant GCSFR signaling effects and their interactions with mutant ELANE;
and Aim 2) Estimate the number, timing, and selective advantage of mutations in granulocyte progenitors at the MDS/AML stages and develop and validate population genetics models to predict risk of transition from SCN?MDS?AML. To accomplish these aims, we have assembled an expert multidisciplinary team in state-of-the-art experimental hematology (high-dimensional mass cytometry, cellular barcoding, and patient-derived iPSC), computational biology, network analysis, and applied probability to develop an innovative multiscale systems analysis of how defective granulopoiesis undergoes malignant transformation. Our goal is to produce a first-generation, multi-scale model for clonal evolution of a sick blood stem cell into an unstable one. Our long-term objectives are to establish patterns of network perturbations in myeloid clonal evolution, predict patient risk fo transformation, and design measures to prevent that life-threatening event. One insight from our modeling is that we can predict when transformation to MDS can occur in patients with SCN, which could be used to optimize surveillance and clinical intervention.
Myelodysplastic Syndromes (MDS) are a group of life-threatening blood disorders that progress to more deadly forms. MDS is increasing in frequency as the population ages. Studying one form of MDS in children, we will use experimental data and computer models to reveal how MDS develops over time. Our studies provide the groundwork for a more accurate understanding of MDS, which hopefully will yield better therapies.
| Corey, Seth J; Jha, Jyoti; McCart, Elizabeth A et al. (2018) Captopril mitigates splenomegaly and myelofibrosis in the Gata1low murine model of myelofibrosis. J Cell Mol Med 22:4274-4282 |
| Goltsev, Yury; Samusik, Nikolay; Kennedy-Darling, Julia et al. (2018) Deep Profiling of Mouse Splenic Architecture with CODEX Multiplexed Imaging. Cell 174:968-981.e15 |
| Corey, Seth J; Oyarbide, Usua (2017) New monogenic disorders identify more pathways to neutropenia: from the clinic to next-generation sequencing. Hematology Am Soc Hematol Educ Program 2017:172-180 |
| Pezeshki, Alex; Podder, Shreya; Kamel, Ralph et al. (2017) Monosomy 7/del (7q) in inherited bone marrow failure syndromes: A systematic review. Pediatr Blood Cancer 64: |
| Matatall, Katie A; Jeong, Mira; Chen, Siyi et al. (2016) Chronic Infection Depletes Hematopoietic Stem Cells through Stress-Induced Terminal Differentiation. Cell Rep 17:2584-2595 |
| Chen, Yolande; Corey, Seth Joel; Kim, Oleg V et al. (2014) Systems biology of platelet-vessel wall interactions. Adv Exp Med Biol 844:85-98 |
| Mehta, Hrishikesh M; Glaubach, Taly; Corey, Seth Joel (2014) Systems approach to phagocyte production and activation: neutrophils and monocytes. Adv Exp Med Biol 844:99-113 |
