My laboratory seeks to understand the biology of blood development, with a special interest in understanding malignant and pre-malignant blood diseases such as Myelodysplastic Sydrome (MDS) and Acute Myelogenous Leukemia (AML). Our eventual goal is to develop novel therapeutic strategies against MDS and AML, or to therapeutically affect the biology of normal blood-forming stem cells.
In most animals, including humans, the cellular elements of blood are likely created out of a blood-forming stem cell, termed the hematopoietic stem cell (“HSC”). HSCs typically reside in the bone marrow in highly specialized microenvironments termed “niches”. In their normal state, HSCs are deeply quiescent, dividing once every 150 days in mice; however, these cells can be activated to divide and differentiate under certain conditions, such as injury or loss of blood. The inappropriate and dysregulated activation of HSCs can lead to cancers of blood, such as Acute Myelogenous Leukemia (AML) and may contribute to diseases such as MDS.
In part, the quiescence of HSCs depends on signals from their environment. Osteoblasts – bone forming cells – provide regulatory signals to HSCs. Thus, there is an intimate connection between bone and bone marrow: bone cells create a “niche” for hematopoietic cells that regulates their function and physiology. This microenvironment is termed a hematopoietic niche. Other cells, such as blood-vessel forming cells, also participate in this niche.
If bone cells regulate the biology of HSCs, could they also regulate malignant and pre-malignant cells that reside in the bone marrow, such as leukemia ?
One project in the lab focuses on understanding the role of this osteoblastic niche in normal HSCs, as well as pre-malignant HSCs. In previous work, in collaboration with David Scadden and Marc Raaijmakers, we showed that alterations in the osteoblastic niche can enable a pre-cancerous condition. In other words, changing the microenvironment alone (using genetic alterations in osteoblasts) can predispose an animal to cancer (in this case, myeloid leukemia or AML). We are now determining the precise role of osteoblasts in this process by characterizing the signals between osteoblasts and HSCs in the bone marrow.
Of particular interest to my lab is a disease called Myelodysplastic Syndrome or MDS. MDS is a complex and heterogeneous set of diseases of blood in which normal blood development does not occur appropriately. A fraction of MDS patients will develop acute myelogenous leukemias (AML). Notably, there are bone abnormalities in some MDS patients. We are therefore studying how alteration of bone biology might influence MDS and leukemia.
What regulates the switch between quiescence and division in HSCs or in MDS ?
We have performed a novel high throughput screen to identify genes that regulate the quiescence of HSCs. We identified 7 new genes in this screen. Studies are underway to determine how these genes affect HSCs or leukemia cells.
What genes are altered in MDS and how do these genes influence the biology of this disease ?
We have sequenced genes and genomes of MDS patients and identified novel mutations in genes previously uncharacterized in this disease. This list includes genes such as DNMT3a, a methyltransferase of unknown function in hematopoiesis. Our lab is now creating mouse models to understand the role of this gene.
Can we therapeutically intervene on the normal HSC niche ?
In collaboration with the Broad Institute of MIT, we have completed a screen of 25,000 chemicals to identify chemicals that can increase or activate HSC function. Studies in the laboratory are addressing the mechanisms by which these chemicals act.