Loss of the Imprinted Gene GRB10 Promotes Leukemia Progression

Acute myeloid leukemia (AML) is a uniformly fatal hematologic disease and, for most AML sub-types, this disease is only curable via allogeneic hematopoietic cell transplantation. Novel approaches to treat and eradicate human AML remain a substantial unmet medical need. AML is a clonal hematopoietic stem cell disorder in which leukemic stem cells (LSCs) drive disease initiation, progression, and relapse. Growth factor receptor bound protein 10 (GRB10) is a regulatory protein that is encoded by a gene within the family of imprinted genes. We previously showed that maternal deletion of GRB10 (GRB10 m/ + mice) substantially increased the competitive repopulation capacity of hematopoietic stem cells in steady state and also increased HSC regenerative capacity following total body irradiation. The role of GRB10 in the pathogenesis of leukemia is yet to be determined. GRB10 has been shown to associate with several transmembrane tyrosine kinase receptors and binds the intracellular portion of low-density lipoprotein receptor-related protein 6 thereby negatively regulating the Wnt/-catenin pathway. Of note, -catenin signaling through Wnt is essential for establishment and long-term maintenance of LSCs. Recent studies implicate Wnt signaling as critical to the drug resistance properties of LSCs in human myeloid leukemia. We sought to interrogate the role of GRB10 in HoxA9 and MLL-driven AML. Using a conditional GRB10 m/ + murine model, we observed that deletion of the maternal allele of GRB10 causes an increase in LSC cell cycle and more rapid leukemia progression in vivo. Similarly, deletion of GRB10 in human AML cell lines caused increased leukemia cell growth and colony forming capacity in vitro. RNAseq analysis of GRB10 m/ + AML mice compared to GRB10 wildtype AML mice revealed significant dysregulation of the canonical Wnt/ catenin signaling pathway. We further determined that Wnt/-catenin target genes, including Myc, Cyclin D1, and Sox2 were significantly upregulated in GRB10 deficient AML cell lines. Taken together, these data suggest that GRB10 is a tumor suppressor gene in AML, and therapies capable of agonizing GRB10 have potential as anti-leukemia agents.