Hedgehog (Hh) proteins are a highly conserved family of intracellular signaling molecules that play critical roles in normal development, self-renewal, and in the development of several cancers. Therefore Hh antagonists are under development as potential therapeutic agents. We recently reported the unexpected finding that loss of Hh signaling through conditional deletion of Smoothened (Smo) has no apparent effect on adult hematopoietic stem cell function and hematopoiesis, and leukemogensis mediated by MLL-AF9. Furthermore, pharmacologic inhibition of Hh signaling with a selective small molecule antagonist had no substantive effect on hematopoiesis in the mouse (Hofmann et al 2009). In contrast recent reports in the literature indicate that Smo is essential for BCR-ABL mediated leukemia (Dierks et al 2008, Zhao et al. 2009). Based on these observations we hypothesize that leukemia associated alleles that do not themselves engender self-renewal potential to committed hematopoietic progenitors such as BCR-ABL and KRAS require Hh signaling for long-term disease maintenance. In contrast, we hypothesize that leukemogenic alleles that can confer properties of self-renewal to committed progenitors such as MLL-AF9 and CDx2 do not require Hh signaling. To test this hypothesis we propose to express the above leukemogenic alleles in a Smo deficient background and assess impact on development, maintenance, and transplantability of leukemia. Furthermore we will use pharmacologic approaches to evaluate whether inhibition of the Hh pathway leads to inhibition of leukemia progression.
The Specific Aims are: 1) To determine if Hh signal transduction is required for leukemic transformation mediated by oncogenes that that do not confer self-renewal potential such as BCR-ABL, and oncogenic KRAS 2) To evaluate whether Hh signaling is dispensable for leukemogenesis mediated by oncogenes that do engender self-renewal potential such as MLL-AF9 and CDX2. 3) To determine whether progression of leukemia induced by BCR-ABL, KRAS or MLL-AF9 can be inhibited by the selective small molecule Hh inhibitor HhAntag in vivo. With support from the K08 Award, Dr. Hofmann Zhang, a Pediatric Hematology/ Oncology instructor at Children's Hospital Boston (CHB) has outlined a 5-year career plan that will build upon her background both in Hematology/Oncology and Hematopathology. Under the co-mentorship of Drs. Scott Armstrong and David Williams, recognized leaders in leukemia, hematopoietic stem cell biology, and translational research, she seeks to utilize a definitive biologically relevant mouse model and pharmacologic approaches to study the role of Hh in leukemogenesis. Dr. Hofmann Zhang will be mentored by an Advisory Committee of internationally recognized experts in the field. Finally, the plan is ideally carried out in the Division of Hematology/Oncology at CHB, given it's distinguished record for training physician-scientists in a rich and collaborative environment.
Developmental pathways such as Wnt, Notch, and Hedgehog (Hh) are essential in regulating tissue and organ development during embryogenesis. Furthermore, Hh has been found to be important in certain aspects of hematopoiesis and in tumorgenesis of several types of cancers. Development of Hh antagonists are currently underway as potential therapeutic agents for several solid tumors. Their potential application in the treatment of leukemia remains unclear. The results that will emerge from this proposal will provide novel insights into the role of the Hh signaling pathway in the development and maintenance of leukemia and will inform us about the specific use of Hh antagonists as potential therapeutic agents for specific leukemias.
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