Chromatin-Spliceosome Mutations in Acute Myeloid Leukemia

Abstract

Recent genetic studies on large patient cohorts with acute myeloid leukemia (AML) have cataloged a comprehensive list of driver mutations, resulting in the classification of AML into distinct genomic subgroups. Among these subgroups, chromatin-spliceosome (CS)-AML is characterized by mutations in the spliceosome, cohesin complex, transcription factors, and chromatin modifiers. Class-defining mutations of CS-AML are also frequently identified in myelodysplastic syndrome (MDS) and secondary AML, indicating the molecular similarity among these diseases. CS-AML is associated with myelodysplasia-related changes in hematopoietic cells and poor prognosis, and, thus, can be treated using novel therapeutic strategies and allogeneic stem cell transplantation. Functional studies of CS-mutations in mice have revealed that CS-mutations typically cause MDS-like phenotypes by altering the epigenetic regulation of target genes. Moreover, multiple CS-mutations often synergistically induce more severe phenotypes, such as the development of lethal MDS/AML, suggesting that the accumulation of many CS-mutations plays a crucial role in the progression of MDS/AML. Indeed, the presence of multiple CS-mutations is a stronger indicator of CS-AML than a single mutation. This review summarizes the current understanding of the genetic and clinical features of CS-AML and the functional roles of driver mutations characterizing this unique category of AML.

Keywords: acute myeloid leukemia; chromatin; cohesin; epigenetic regulation; hematopoiesis; myelodysplastic syndrome; splicing factor.

Figure 1

Definition and genetic features of chromatin-spliceosome acute myeloid leukemia (CS-AML). Scheme demonstrating the definition of CS-AML.

Figure 2

Splicing factors (SFs) and alternative splicing affected by mutations. (A) SFs frequently affected in myeloid malignancies and their functions in RNA splicing. (B) Types of alternative splicing events detected in SF-mutated leukemias. snRNP, small nuclear ribonucleoprotein; ESE, exonic splicing enhancer.

Figure 3

Cohesin complex and the 3D genome structure affected by cohesin and RUNX1 mutations. (A) Cohesin complex and its components frequently mutated in myeloid malignancies. (B) Scheme demonstrating the perturbation of short-range loops and deregulation of a subset of genes caused by loss of STAG2 and RUNX1 [22].

Figure 4

CS-mutations in AML. Heatmap representing CS-mutations found in a previous study [6]. Blue bars on the right show the frequency of each mutation in a large cohort of patients with AML (1540 cases). Not all cases demonstrated here satisfy the definition of CS-AML, as a subset of AML with CS-mutations is excluded from CS-AML due to presence of other class-defining mutations, as shown in Figure 1.

Figure 5

CS-mutations in MDS/sAML. A heatmap representing the mutations found in a large cohort of MDS, related myeloid disorders, and sAML, as shown in our previous study [22]. Blue bars on the right show frequencies of mutations in all cases. MPN, myeloproliferative neoplasm; NA, not available.