Research

Ringsideroblasts in primary SF3B1 mutant MDS bone marrow and the corresponding MDS engrafted humanized mice

Splicing Factor Mutations in Myeloid Malignancies
We seek to understand the role of mutations in splicing factors (SFs), present in nearly 50% of patient with MDS and a subset of patients with AMLs. Mutations in SFs are not only recurrent in nature, affecting specific amino acid positions, but also mutually exclusive; patients carry mutations in only one splicing factor. This suggests a common mechanism in the pathogenesis of MDS. We employ structural, molecular biology, and multi-omic approaches, and in vivo xenotransplantation to determine disease mechanism and develop novel therapeutics.
m6A RNA modifications in Hematopoiesis
N6-methyladenosine is the most abundant RNA modification and plays key roles in RNA metabolism affecting transcript stability and translation efficiency. We are interested in understanding the detailed mechanisms by which m6A affects normal and malignant hematopoiesis. We employ genetically engineered mouse models and RNAseq, eCLIP, and ribosome profiling to dissect the role of m6A in hematopoietic stem cell maintenance, differentiation, and leukemogenesis. We discovered that loss of METTL3 and the m6A RNA modification results in the aberrant formation of double stranded RNA and activation of a deleterious innate immune response. We treasure numerous collaborations within Yale's RNA Center to apply cutting edge technologies and deep understanding of RNA biology to hematologic disorders.
Co-clinical Mod els for the study of hematopoiesis, bone marrow failure, MDS/AML, and hemoglobinopathies.
MDS and AML are inherently difficult to study. They are heterogeneous diseases; only rare human cell lines have been successfully derived from patients’ MDS and few from patients with AML; hematopoietic and leukemic stem cells (HSC/LSC) do not grow in culture and MDS stem cells fail to efficiently engraft even in the best currently available mouse models. In collaboration with the Flavell laboratory we have developed the first highly efficient xenotransplantation model for MDS in the humanized MISTRG mice amenable to drug treatments. We continue to improve upon this model to extend our studies to diseases of red cell production and the human immune system. We are collaborating with the Fan lab in the Yale Biomedical Engineering Department and the Grimes lab at Cincinnati Children's Hospital to generate multi-omic maps of MDS and AML in their microenvironments.
Hematology Tissue Bank
The Hematology Tissue Bank has been established to give researchers access to critical patient samples for the study of hematologic diseases. This biorepository was designed to support biomedical research including clinical trials, support focused research, and serve community health initiatives. The overarching goals are to better understand and treat blood disorders to find better ways to detect blood disorders early, determine how certain blood disorders may spread and resist current types of treatment, to find out how well different therapies work, and to treat and, if possible, cure patients who have these disorders. Should you wish to obtain samples for your research contact Martin Matthews (martin.matthews@yale.edu), Jennifer VanOudenhove (Jennifer.vanoudenhove@yale.edu) and Stephanie Halene (stephanie.halene@yale.edu).
Mouse Modeling Core (AMC) – Yale Center for Excellence in Hematology (YCCEH)
The Mouse Modeling Core, directed by Richard Flavell and Stephanie Halene, is part of the YCCEH with the goal to provide researchers with access to the latest technologies for hematologic studies in animal models. The core offers expertise, technical assistance, and mice for human-into-mouse xenotransplantation studies. It offers training and technical assistance in the study of hematopoiesis and benign hematologic questions in mice.