Identification and Targeting of Microenvironmental Factors Controlling Pediatric Leukemia
T cell acute lymphoblastic leukemia (T-ALL) is a devastating pediatric blood cancer. Despite progress in treating T-ALL, a quarter of childhood patients relapse within five years and receive a bleak prognosis. The general toxicity associated with recent therapeutic efforts to treat T-ALL stresses the urgent need for novel innovative therapies. While much is known about the genetics of leukemic cells, little is understood about how they behave within their native milieu, the bone marrow. Several lines of evidence indicate the leukemia cells require a specialized microenvironment to survive, and that disrupting this microenvironment may be a novel, promising therapeutic strategy. Our recent work identified CXCL12, which produces the vascular endothelial cells that constitute the blood vessel network, as a necessary component of a leukemic niche in the bone marrow. Given that leukemic cells cannot produce CXCL12, they rely on blood vessels for their supply of CXCL12. We found that interrupting this supply after disease onset dramatically reduced leukemic burden, suggesting a potential new therapeutic paradigm to treat this devastating disease.
Our proposed studies will: 1) examine which other molecular factors produced by the microenvironment are important for leukemia development, and 2) test the therapeutic potential of CXCL12 blockade. This will be one of the first examples of therapeutic targeting of the cancer microenvironment in leukemia. Understanding the role of the microenvironment in the development and maintenance of this blood cancer will suggest novel and effective therapeutic strategies to treat this devastating disease.