PRMT1-RBM15 axis regulates megakaryocytic differentiation of human umbilical cord blood CD34+ cells

Abstract

Abstract. Protein arginine methyltransferase 1 (PRMT1) serves pivotal roles in various cellular processes. However, its role in megakaryocytic differentiation has not been clearly reported. The aim of the present study was to explore the role of the PRMT-RNA binding motif protein 15 (RBM15) axis in human MK differentiation and the feasibility of targeting PRMT1 for leukemia treatment. In the present study, PRMT1 was overexpressed and the RBM15 protein was knocked down in human umbilical cord blood cluster of differentiation (CD)34 + cells and the cells were then cultured in megakaryocytic differentiation medium. Flow cytometry was used to analyze CD41 and CD42 double-positive cells, as well as the protein expression levels of PRMT1 and RBM15. The results demonstrated that human cord blood CD34 + cells differentiate into mature MKs in high thrombopoitin medium, as demonstrated by CD41 and CD42 expression. Overexpression of PRMT1 in human umbilical cord blood CD34 + cells blocked the maturation of megakaryocytic cells. Knockdown of RBM15 by short hairpin RNA produced less mature MKs. PRMT1 inhibitor rescued PRMT1-blocked megakaryocytic differentiation. These results provide evidence for a novel role of PRMT1 in the negative regulation of megakaryocytic differentiation. PRMT1 may be a therapeutic target for leukemia treatment.

Protein arginine methyltransferase 1 is required for maintenance of normal adult hematopoiesis

“…Additionally, through histology analysis of BM, we did find increased number of megakaryocytes. Our result is in agreement with others study, showing PRMT1 overexpression antagonized megakaryocytic differentiation [28]. However, in our mouse studies, we found PRMT1 KO did not affect platelet level.…”

RNA-binding proteins in tumor progression

“…In acute megakaryoblastic leukemia, the protein arginine methyltransferase 1 (PRMT1) is highly expressed and can methylate R578 residue on RBM15 and promotes PRMT1 ubiquitination-mediated degradation by E3 ligase (CNOT4). Notably, RBM15 can regulate a series of genes related to megakaryocyte production [90,91]…”

“…In acute megakaryoblastic leukemia, the protein arginine methyltransferase 1 (PRMT1) is highly expressed and can methylate R578 residue on RBM15 and promotes PRMT1 ubiquitination-mediated degradation by E3 ligase (CNOT4). Notably, RBM15 can regulate a series of genes related to megakaryocyte production [ 90 , 91 ]. RBP’s PTMs are involved in important biological processes, including carcinogenesis, apoptosis, tumorigenesis and cancer progression, cell division and cell response to stress drugs.…”

Megakaryocyte Progenitor Cell Function is Enhanced Upon Aging Despite the Functional Decline of Aged Hematopoietic Stem Cells

“…Also, previously described regulators of megakaryocyte differentiation were differentially expressed. These genes include Prmt1, Selp, and Tesc, a regulator of E26 transformation-specific (ETS) transcription factors (Levay and Slepak, 2007;Jin et al, 2018;Banu, Avraham and Karsenty, 2020). We also observed differential expression of multiple genes associated with Plt regulation, production, and function: Coagulation Factor X, Dtnbp1, Gfi1b, Enpp4, Pafah1b3, Pafah1b1, Mmrn1, and Selplg.…”