Poster Presentation 30th Lorne Cancer Conference 2018

Novel G protein-coupled receptor regulating self-renewal in leukemia stem cells - a potential therapeutic target (#253)

Basit Salik 1 , Hangyu Yi 1 , Patrick Connerty 1 , Jeannie Lim 1 , Jenny Wang 1
  1. Children's Cancer Institute, Randwick, NSW, Australia

Acute myeloid leukemia (AML) is an aggressive leukemia characterized by the maturation arrest of myeloid cells and rapid accumulation of immature blasts. AML accounts for the first and second most common forms of leukemia in adults and children respectively. Despite the availability of effective chemotherapies, cancer relapse is a commonly observed phenomenon. A small percentage of cells termed ‘cancer stem cells’ drive malignant transformation of tumors via an aberrant activation of key self-renewal pathways crucial for stem cell malignancy in various cancers. In AML, we have previously demonstrated that Wnt/β-catenin signaling is important for the development of leukemic stem cells (LSCs). LSCs and their precursor pre-LSCs have the ability to self-renew, initiate and maintain leukemia upon serial transplantation in animal models. Wnt/β-catenin self-renewal pathway is of particular interest as it is important for LSCs but not critical for the self-renewal of adult hematopoietic stem cells (HSCs), allowing it to be an attractive therapeutic target. However, its key pathway components remain largely unknown. Here we show that Lgr4/ β-catenin  signaling is a key determinant in sustaining high LSC self-renewal in vivo and its constitutive activation is pro-leukemogenic. Lgr4 positively regulates β-catenin signaling during the LSC development in AML. Our data show that Lgr4 depletion impairs LSC self-renewal and therefore significantly delays leukemia onset in murine and xenograft models of AML. Inhibition of this previously unrecognized signaling cascade offers a new therapeutic opportunity for AML.