Chromatin-Spliceosome Mutations in Acute Myeloid Leukemia

SIMPLE SUMMARY: Recent genomic studies have identified chromatin-spliceosome (CS)-acute myeloid leukemia (AML) as a new subgroup of AML. CS-AML is defined by several mutations that perturb epigenetic regulation, such as those affecting splicing factors, cohesin components, transcription factors, and chromatin modifiers, which are also frequently mutated in other myeloid malignancies, such as myelodysplastic syndrome and secondary AML. Thus, these mutations identify myeloid neoplasms that lie on the boundaries of conventional differential diagnosis. CS-AML shares several clinical characteristics with secondary AML. Therefore, the presence of CS-mutations may help to better classify and manage patients with AML and related disorders. The aim of this review is to discuss the genetic and clinical characteristics of CS-AML and roles of driver mutations defining this unique genomic subgroup of AML. 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.