Department of Human Genetics
Ongoing Projects //
1- The contribution of epigenetically silenced genes to leukemogenesis
In the Figueroa lab’s previous work they identified the existence of a core set of genes recurrently silenced through hypermethylation in primary human acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). These genes are universally silenced across all AML and MDS patients, irrespective of their classification subtype and the genetic lesions underlying the disease. They hypothesized that silencing of this core set of genes represents an early and necessary event in myeloid malignant transformation. Using a combination of functional genomic screens in vivo and in vitro as well as single-gene mechanistic approaches the Figueroa lab is studying the contribution of each these genes to normal and malignant hematopoiesis, as well as their potential for therapeutic targeting.
2- Epigenetic deregulation in MDS
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders characterized by ineffective hematopoiesis and increased risk of transformation to AML that occur in the elderly population. Despite molecular, morphological and clinical heterogeneity, MDS cases are uniformly characterized by aberrant DNA methylation profiles and the only proven therapy for these disorders are DNA methyltransferase inhibitors (DNMTi), which have proven effective in 30-40% of patients. However, little is known of how epigenetic deregulation contributes to MDS development and phenotype determination or why only a subset of these patients respond to epigenetic therapies. In the lab they are using primary human MDS specimens and studying them using genome-wide studies to identify candidate genes and pathways involved in determining disease progression and response to DNMTi, followed by functional testing in vitro and in vivo in murine models of candidate genes and pathways. Through their genome-wide approaches the Figueroa lab has identified the chemokines CXCL4 and CXCL7, which are upregulated in DNMTi-resistant patients and have previously been reported linked to chemoresistance of conventional chemotherapeutic agents. Mechanistic studies of how these genes contribute to DNMTi resistance are currently underway in the lab.
3- The role of the aging epigenome in normal and malignant myelopoiesis.
The frequency of myeloid malignancies increases significantly with every decade of age, and while rare in young adults and children, they are frequently observed in the elderly. Thus, it is likely that age-related changes in the form of genomic or epigenetic abnormalities may contribute to this increased susceptibility to MDS and AML in the elderly. DNA methylation becomes deregulated with aging and to some extent these age-related changes are similar in nature to those observed in malignant scenarios. The Figueroa lab hypothesizes that increasing disruption with age of normal epigenetic patterns in the hematopoietic system lay the foundation for the development of MDS and AML in elderly patients. They are studying DNA methylation, hydroxymethylation, chromatin modifications, and gene expression patterns in human hematopoietic cells during normal aging and comparing them to those observed in patients with MDS. The Figueroa lab seeks to (i) understand how the epigenome changes in the hematopoietic system as people age, (ii) identify specific epigenetic abnormalities which are acquired during aging and which may play a pathogenic role in the development of MDS.