Activation of Anti-Leukemia Immunity by Targeting Protein Arginine Methyltransferase
Childhood acute myeloid leukemia (AML) patients harboring a genetic change called “MLL gene rearrangement (MLL-r)”, have a particularly poor outcome, with a five-year survival rate ~56%. Those patients, accounting for ~15% of all childhood AML patients, are associated with high risk of disease come-back. Currently, immunotherapies, which mobilize a patient’s own T cells to eliminate cancer cells, have proven effective against other pediatric leukemias, particularly acute lymphoblastic leukemia. However, currently available immunotherapy approaches have been less effective against childhood AML, including the MLL-r subtype. Thus, there is a pressing need to develop immunotherapies effective against these AML children. Recently, several biology studies from others have shown that stimulating a signaling pathway known as cGAS-STING can induce a strong anti-tumor immune response against solid tumors. Herein, our preliminary study in an AML mouse model driven by an MLL-r fusion gene called “MLL-AF9” (seen in ~50% pediatric MLL-r AML) showed that downregulating a gene called PRMT9 promotes the cGAS-STING signaling and blocks disease development. Moreover, we also developed a small molecule compound that decreases PRMT9 activity, and combining this compound with conventional immunotherapy (namely, a PD1 inhibitor) eradicated the aggressive mouse and human AML. We propose that our new PRMT9-targeting drug could be developed as an anti-AML therapy and tested either alone or combined with other immunotherapies in future clinical trials.
Project Goals:
The goal of this proposal is to devise effective therapy for a hard-to-treat subtype of pediatric AML known as “MLL-r AML”. Current anti-AML drugs cannot eradicate AML cells completely. So far, the most effective treatment option for AML is allogeneic hematopoietic stem cell transplantation (alloHSCT), a type of immunotherapy that supplies T cells from a donor to kill leukemia cells. However, alloHSCT has side effects, and much safer and effective treatments for children with AML are greatly needed. We have preclinical data showing that an enzyme called PRMT9 drives leukemia development by shielding them from eradication by the immune system. Here, we will define how cancer cells’ PRMT9 blocks anti-leukemia immunity using genetically-modified AML model mice (Aim 1). In Aim 2, we will define PRMT9 downstream targets that when unmethylated underlie cGAS activation in cancer cells. Our preliminary studies also show that decreasing PRMT9 activity synergizes with an existing FDA-approved immunotherapy drug known as PD1-antibody to eradicate cancer cells in a syngeneic AML mouse model. Thus, in Aim 3, we will refine the regimen of our newly developed PRMT9 inhibitor and then test the effectiveness of combining it with PD1-antibody against AML in human AML relevant models. If successful, these approaches could soon be tested in clinical trials. Development of these strategies could eradicate MLL-r AML and improve outcomes for all pediatric AML patients, given that relative to normal cells, PRMT9 expression is significantly elevated in leukemia cells from all subtypes of the disease.
