RNA modifications in hematopoietic malignancies: a new research frontier

Abstract

Protein-coding and noncoding RNAs can be decorated with a wealth of chemical modifications, and such modifications coordinately orchestrate gene expression during normal hematopoietic differentiation and development. Aberrant expression and/or dysfunction of the relevant RNA modification modulators/regulators ("writers," "erasers," and "readers") drive the initiation and progression of hematopoietic malignancies; targeting these dysregulated modulators holds potent therapeutic potential for the treatment of hematopoietic malignancies. In this review, we summarize current progress in the understanding of the biological functions and underlying mechanisms of RNA modifications in normal and malignant hematopoiesis, with a focus on the N6-methyladenosine modification, as well as discuss the therapeutic potential of targeting RNA modifications for the treatment of hematopoietic malignancies, especially acute myeloid leukemia.

Graphical abstract

Figure 1.

Deposition, removal, and recognition of m⁶A modification. The m⁶A modification is deposited by “writers” that function as a complex or as a single protein (METTL16). The MTC consists of 3 key components (METTL3, METTL14, and WTAP) and several auxiliary subunits (including RBM15/15B, KIAA1429, and ZC3H13). Two m⁶A demethylases, FTO and ALKBH5, serve as “erasers” and can reverse m⁶A to A in an α-ketoglutarate (α-KG)-dependent way. Notably, R-2-hydroxyglutarate (R-2HG), a metabolite produced by mutant isocitrate dehydrogenase, is reported to competitively suppress the demethylase activity of FTO as a result of its similar structure to α-KG. The broad biological functions of m⁶A are mediated by “readers” that are able to recognize the methyl group or m⁶A-induced structural changes (“the m⁶A switch”) to regulate gene expression of downstream targets. Currently known readers include the YTH family (YTHDF1/2/3 and YTHDC1/2), the IGF2BP family (IGF2BP1/2/3), and other proteins (eg, hnRNPA2B1, hnRNPC, and hnRNPG) that recognize m⁶A switches.

Figure 2.

Roles of m⁶A in normal hematopoiesis. In the process of normal hematopoiesis, m⁶A regulators can play promoting (green arrows) or inhibitory (red bars) roles at various stages. Specifically, METTL3 promotes the generation of HSCs, and METTL3 and METTL14 promote the self-renewal activity of HSCs. Another component of the m⁶A writer complex, RBM15, suppresses the transition of long-term HSCs to short-term HSCs. The 3 key subunits of the m⁶A writer complex, METTL3, METTL14, and WTAP, promote erythroid differentiation. In contrast, METTL3, METTL14, and RBM15 inhibit the myeloid differentiation of HSCs in normal hematopoiesis. The m⁶A reader YTHDF2 suppresses the self-renewal activity of HSCs. The identified downstream effectors (signaling pathways and target proteins) or mediator proteins that are critical for the function of m⁶A regulators are listed (in italics). CMP, common myeloid progenitor; HEC, hemogenic endothelial cell.

Figure 3.

Roles of m⁶A in myeloid leukemogenesis. In the process of myeloid leukemogenesis, multiple m⁶A regulators play oncogenic roles (green arrows) at different stages of leukemogenesis. METTL3 and METTL14 promote the self-renewal/proliferation of leukemia stem cells/leukemia-initiating cells (LSCs/LICs) and the proliferation/survival of leukemia cells. The RBM15-MKL1 fusion protein plays a role in acute megakaryoblastic leukemia, facilitating the transformation of megakaryocytes and inducing a differentiation bias toward the megakaryocytic lineage. WTAP promotes the proliferation of leukemia cells. FTO and ALKBH5 promote the transformation of HSCs to LSCs/LICs, maintain the self-renewal capacity of LSCs/LICs, and are required for the survival/proliferation of leukemia cells. YTHDF2 is essential for leukemia initiation and the functional integrity of LSCs/LICs. The identified downstream effectors (signaling pathways and target proteins) or mediator proteins that are critical for the function of m⁶A regulators are listed (in italics).

Figure 4.

Roles of other RNA modifications in normal and malignant hematopoiesis. In addition to m⁶A, other RNA modifications, such as A-to-I editing, m⁵C, and pseudouridine (ψ), are implicated in normal and malignant hematopoiesis. Specifically, ψ synthase is essential for efficient HSC differentiation, and ψ is highly excreted in urine in AML and chronic myeloid leukemia (CML). Increased levels of m⁵C and its writers confer chemoresistance to MDS/AML cells, m⁵C writers are positively associated with MDS/AML progression, and m⁵C eraser TET2 promotes infection-induced myelopoiesis. The writer for A-to-I editing is required for maintenance of HSCs and survival of hematopoietic progenitor cell (HPCs), whereas the same writer promotes transformation of myeloid progenitors into LSCs/LICs and enhances LSC/LIC self-renewal activity. The level of A-to-I editing is positively correlated with CML progression.