Our research topics are related to disorders affecting blood production. Unrevealing the molecular pathomechnsim of those disorders is important for understanding of basic cellular pathways involved in hematopoiesis and eventually improving patient care.
The role of codanin-1 in erythropoiesis
Congenital dyserythropoiesis type I (CDAI) is a rare inherited disease characterized by macrocytic anemia, ineffective erythropoiesis and pathognomonic cytopathology of nucleated red blood cells in bone marrow. Our group identified that the mutated gene is CDAN1, encoding for Codanin-1 protein. Experimental data suggest that codanin-1 interacts with known regulators of mitosis and chromatin structure to facilitate normal cell division and gene expression. Furthermore, we demonstrated that codanin-1 physically binds anti-silencing function protein 1 homolog A (Asf1a), a histone chaperone involved in post replication nucleosome assembly.
Our current aim is to study the cellular role of codanin-1 in erythropoiesis.
For this purpose we created 2 models:
1. Inducible conditional gene targeting of CDAN1 in mice using an erythropoietin receptor Cre. Those mice die of severe anemia on days E11.5-13.5 intrauterine demonstrating progressive dyserythropoiesis
starting at day E10.5
2. Human erythroblasts 2-phase liquid culture system from CDAI patients. We currently studying genes involved in cell cycle during erythropoiesis and plan to study transcriptome and single cell transcriptome of different stages of erythropoiesis in both disease models in comparison to controls.
Genomic and functional studies of patients with inherited predisposition to myelodysplastic syndrome
(In collaboration with Prof Akiko Shimamura Director, Bone Marrow Failure& MDS Program : Boston Children’s Cancer and Blood Disorders Center).
Myelodysplastic syndrome (MDS) is a clonal hematopoietic disorder characterized by ineffective hematopoiesis and propensity to evolve to acute leukemia. Recent studies show that in addition to the increased risk of MDS associated with inherited bone marrow failure (IBMF), inherited predisposition to MDS may present without antecedent marrow failure. Accurate diagnosis of inherited MDS carries profound implications for medical management including the need for hematopoietic stem cell transplant (HSCT) before progression to leukemia, and for genetic testing of family member donors before HSCT to avoid choosing a donor carrying the same germline mutation(s) as the proband.
The aim of this study is to identify new genes involved in inherited myelodysplastic syndrome (primary or secondary to IBMF )
We already identified 10 children and young adults (half from consanguineous families) with highly suspected inherited MDS for whom mutations in known IBMF/MDS genes were not identified by targeted NGS panel or whole exome sequencing (WES). Candidate pathogenic mutations in novel genes were identified in 2 families of this cohort. We plan to study these candidate genes and to evaluate the ‘exome negative’ patients using different analytic pipelines and orthogonal methodologies. For all new genes identified by this systematic approach, functional consequences will be evaluated using human models of hematopoiesis. Our work will not only improve diagnosis and inform medical management of children and young adults with predisposition to MDS but also will provide insights into global molecular pathways regulating hematopoiesis and malignant transformation.