SETD2 Mutations Cooperate with Chromosomal Aberrations in Leukemia

Chromosomal rearrangements are present in over 50% of acute leukemias but are insufficient for full disease development. To define cooperative mechanisms between gross chromosomal alterations and additional genetic or epigenetic changes driving leukemogenesis, Zhu and colleagues studied hematopoietic cells from a pair of monozygotic twins, one of whom had MLL translocation-associated acute myeloid leukemia (AML). Expression of MLL–NRIP3, the fusion gene resulting from the MLL rearrangement, in mouse hematopoietic cells induced leukemia with a median latency of 46.5 days, suggesting the requirement for additional genetic events. Indeed, whole-genome sequencing of the twin samples uncovered biallelic point mutations in SETD2, which encodes an enzyme that trimethylates histone H3 lysine 36 (H3K36me3), an epigenetic mark involved in transcriptional elongation. Sequencing of SETD2 in an additional 241 primary AML and acute lymphoblastic leukemia patient samples revealed 19 somatic SETD2 mutations in 15 patients, with a significantly higher frequency in patients with MLL-rearranged leukemia, although SETD2 mutations coexisted with additional major genetic aberrations in the majority of patients. SETD2 mutations were biallelic in 4 of the 15 patients, often caused truncation of the domain responsible for SETD2 recruitment to target genes, and were associated with global H3K36me3 loss in leukemia cells. SETD2 knockdown in preleukemic mouse cells led to decreased H3K36me3 and conferred a significant growth advantage through activation of leukemia-promoting signaling pathways such as mTOR. In addition to a role in leukemia initiation, SETD2 loss in conjunction with MLL translocations contributed to the progression of leukemia through an enhanced self-renewal gene expression signature in leukemic stem cells. Taken together, these results implicate SETD2 as a tumor suppressor gene and demonstrate that loss-of-function SETD2 mutations can facilitate the initiation and maintenance of leukemias with chromosomal translocations through a global reduction of H3K36me3.

Zhu X, He F, Zeng H, Ling S, Chen A, Wang Y, et al. Identification of functional cooperative mutations of SETD2 in human acute leukemia. Nat Genet 2014 Feb 9 [Epub ahead of print].