Journal of Blood & Lymph

Targeting Protein Arginine Methyltransferase 1 Blocks RBM15-MKL1 Fusion-Initiated Human Stem Cell Transformation

Abstract

Jin S, Yao Z, Mi Y, Wang H, Yao S, Song J, Zhang P, Zhang J, Zhou W, Ma J, Guo Y and Liu Y*

Objective: The chromosome translocation t (1;22), which generates the RBM15-MKL1 fusion gene, is found in approximately 10% of pediatric acute megakaryoblastic leukemia cases. Given that PRMT1 downregulation is critical for megakaryocyte differentiation, we propose the use of the PRMT1 inhibitor furamidine to stimulate RBM15- MKL1-transformed human cord blood cells to undergo megakaryocyte differentiation. Materials and methods: Human CD34+ cells were purified from umbilical cord blood with anti-CD34 magnetic beads. Lentivirus-infected CD34+ cells were sorted using flow cytometry. The methylcellulose colony replating assay was performed to evaluate the transformation efficiency. Cell viability was calculated using a CellTiter-Glo® luminescent cell viability assay kit. Results: The simultaneous transduction of RBM15-MKL1 and MPLW515L, a mutated MPL gene found in AMKL patients, into human CD34+ cells resulted in long-term growth in the presence of a cytokine mix that maintains a population of hematopoietic stem progenitor cells. Elevated expression of PRMT1 was detected in cells transduced with RBM15-MKL1 together with MPLW515L. The PRMT1 inhibitor furamidine (aka DB75) reversed the inhibition of RBM15-MKL1-mediated megakaryocytic differentiation and impeded the replating capability of the transformed cells. Conclusion: PRMT1 facilitates the transformation induced by RBM15-MKL1, and inhibiting PRMT1 activity promotes MK differentiation. Given that furamidine has been used for treating trypanosomiasis in clinical trials and proven to be safe, using furamidine to treat AMKL may be a new curative option for RBM15-MKL1-associated leukemia.