Signaling Pathways in MLL
Translocations involving the mixed lineage leukemia (MLL) gene on chromosome 11q23 are found in both acute myeloid and lymphoid leukemia. The most common MLL translocation in AML fuses the MLL gene with the AF9 gene on chromosome 9p22. We recently demonstrated that human hematopoietic stem cells engineered to express this MLL-AF9 fusion protein develop into leukemia after transplantation into immunodeficient mice. The microenvironment influences whether the leukemia develops with characteristics of a myeloid or lymphoid lineage. This model is based on the cell of origin in human leukemia and provides a useful system to study the relevant genetic and epigenetic changes in MLL-rearranged leukemia.
Frequently, AML with recurrent translocations such as t(9:11) also contain additional common mutations. We are currently taking advantage of our unique system to examine the effects of expressing common AML oncogenes such as N-ras and Flt3-ITD. By studying the molecular signals downstream of these mutations, we can gain insights into how these mutations cooperate in leukemogenesis and how these specific forms of the disease might be better treated.
Within the bulk population of acute myeloid leukemia (AML) blasts there is a subset of leukemic stem cells (LSCs) thought to initiate and perpetuate the clone. Other cells differentiate or bear limited potential for proliferation, suggesting that eradication of the LSC is the relevant goal of therapy. Understanding the signaling pathways involved in the LSC may reveal important therapeutic targets.
Members of the Rho GTPase family of signaling proteins play critical roles in the biology of normal hematopoietic stem cells, including cell growth, survival, adhesion, migration, cytoskeleton changes and retention within the bone marrow microenvironment. Using our model of MLL-AF9 leukemia, we are investigating whether small Rho GTPases, such as Rac, Rho and Cdc42, are similarly relevant in the leukemic stem cell, and whether inhibition of these signaling pathways represents a rational therapeutic strategy.