Chromosome translocation t(1;22)(p13;q13), which is found exclusively in infants with acute megakaryoblastic leukemia (AMKL), yields a fusion gene, RBM15-MKL1 (aka OTT-MAL). Infant AMKL is a fatal disease with poor prognosis. Therefore, finding an effective treatment for this type of AMKL is urgent. Mice expressing Rbm15-MKL1 from the endogenous Rbm15 promoter develop AMKL with long latency (>1 year), suggesting additional molecular changes are necessary to cause rapid progression of AMKL in human. Given that no additional recurrent DNA mutation has been found in AMKL, we propose that constitutively active PRMT1 (activated by c-MPLW515L) might be the driving force for AMKL progression. In this proposal we will use bone marrow transplantation model to test whether PRMT1 can cooperate with RBM15-MKL1 to cause rapid leukemia progression and how PRMT1 reprograms metabolic pathways such as fatty acid oxidation pathway (FAO) in the course of leukemia progression via metabolomics analysis. We plan to accomplish this project via two specific aims:
Aim 1 : To determine whether PRMT1-mediated metabolic reprogramming is a driver for RBM15-MKL1-initiated AMKL. 1.1) We will test whether overexpression of PRMT1 will bypass the requirement for c- MPLW515L to accelerate tumor progression in animal bone marrow transplantation models. 1.2) We will establish the correlation between metabolic reprogramming and disease progression in animal models and in human CD34+ cells immortalized with RBM15-MKL1 and PRMT1 using metabolomics analysis.
Aim 2 : Determine the feasibilities of inhibiting PRMT1 or fatty acid oxidation as new therapeutic strategies. 2.1) We plan to use small molecule inhibitors against fatty acid oxidation to probe the role of FAO in RBM15-MKL initiated AMKL associated with overexpressed PRMT1 or c-MPLW515L. 2.2) We plan to assess whether PRMT1 inhibitors to block AMKL progression. We will further examine metabolomics data from PRMT1 inhibitor treated cells to establish causal correlation.
This proposal is to discover the mechanisms of leukemia progression in acute megakaryoblastic leukemia (AMKL) with RBM15-MKL1 translocation, which is a fatal disease in infants. To accomplish this proposal might lead to potential new therapies by targeting protein arginine methyltransferases (PRMT1) or metabolic pathways regulated by PRMT1.
| Su, Hairui; Sun, Chiao-Wang; Liu, Szu-Mam et al. (2018) Defining the epigenetic status of blood cells using a cyanine-based fluorescent probe for PRMT1. Blood Adv 2:2829-2836 |
