Epigenetic regulation of self-renewal pathways in hematopoietic and leukemic stem cells
Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children. Despite the treatment advances in childhood ALL, numerous important biologic and therapeutic questions need to be answered to achieve the goal of curing every child with ALL. It is believed that leukemias are maintained by a small population of leukemic stem cells that represent a key target for novel curative therapies. I have recently used an unbiased genetic screen to identify the histone demethylase KDM2B as a novel oncogene linked to the induction of hematopoietic malignancies in rodents and to the development of ALL in humans. Manipulation of endogenous KDM2B promotes genome-wide epigenetic changes and alters the expression of genes involved in cell proliferation, survival, and differentiation. Correspondingly, my preliminary data suggest that KDM2B plays important roles in stem cell biology, contributing to stem cell self-renewal and facilitating cellular immortalization in vitro. I propose to study the role of the novel oncogene KDM2B in the initiation and progression of Acute Lymphoblastic Leukemia focusing on its role in the epigenetic regulation of normal hematopoietic and leukemic stem cells. Deciphering of the molecular mechanisms by which KDM2B induces oncogenesis may lead to new therapeutic approaches for the treatment of ALL.
Project Update (February 2016)
Alex Tzatsos answered some questions about the progress of his project.
In simple terms, what do you study and what did you discover?
Our laboratory studies the molecular pathways that regulate normal and malignant hematopoiesis by using genetically engineered mouse models. We are particularly interested in a class of molecules known as histone demethylases that play instrumental roles in genome interpretation. Considering these enzymes are frequently deregulated in pediatric leukemias, they represent a promising new area of research and are candidates for the development of small molecule inhibitors. We discovered that histone demethylase KDM2B is highly expressed in hematopoietic stem cells, and is indispensable for the development and maintenance of the hematopoietic system in mice. Furthermore, we showed that KDM2B functions as a molecular switch that favors lymphoid and counteracts myeloid commitment and deregulation of this switch facilitates leukemic transformation. Our results highlight how an imbalance in cell fate decisions can be linked to cell transformation.
What makes this discovery exciting or interesting?
In normal hematopoiesis a very small population of cells, known as hematopoietic stem cells, gives rise to all blood cells through differentiation to the different lineages. The maintenance and lineage commitment of hematopoietic stem cells are imperative for normal hematopoiesis. A hallmark of childhood leukemias is a block in this differentiation process which leads to accumulation of immature progenitors, and facilitates malignant cell transformation in the context of additional genetic and epigenetic changes. We discovered that KDM2B is not only involved in the maintenance of hematopoietic stem cells, but it also functions as a molecular switch of lymphoid or myeloid lineage commitment. In cancer, this switch is hijacked and facilitates the formation of “leukemic stem cells” that are resistant to current treatments. Although further studies are needed to delineate the complexity of those circuitries, it is becoming evident that restoring differentiation is a promising therapeutic approach which will render “leukemic stem cells” vulnerable to current therapies.
Why did you get into cancer research?
Being trained as a medical doctor, I have experienced firsthand not only the challenges that children and their families are faced with, but also challenges that doctors experience when effective therapies are lacking. I decided to expose myself to basic research hoping to contribute to our understanding of the molecular changes that lead to cancer development and improve current therapies.
Where do you go from here – what are your next steps?
The next step in our research is to use our mouse models as in vivo platforms to test the efficacy of small molecule inhibitors that target KDM2B.
2016 Publication in the Journal of Clinical Investigation: Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis.