SETD2 alterations impair DNA damage recognition and lead to resistance to chemotherapy in leukemia

Abstract

Mutations in encoding the histone 3 lysine 36 trimethyltransferase, are enriched in relapsed acute lymphoblastic leukemia and MLL-rearranged acute leukemia. We investigated the impact of mutations on chemotherapy sensitivity in isogenic leukemia cell lines and in murine leukemia generated from a conditional knockout of mutations led to resistance to DNA-damaging agents, cytarabine, 6-thioguanine, doxorubicin, and etoposide, but not to a non-DNA damaging agent, l-asparaginase. H3K36me3 localizes components of the DNA damage response (DDR) pathway and mutation impaired DDR, blunting apoptosis induced by cytotoxic chemotherapy. Consistent with local recruitment of DDR, genomic regions with higher H3K36me3 had a lower mutation rate, which was increased with SETD2 mutation. Heterozygous conditional inactivation of in a murine model decreased the latency of MLL-AF9-induced leukemia and caused resistance to cytarabine treatment in vivo, whereas homozygous loss delayed leukemia formation. Treatment with JIB-04, an inhibitor of the H3K9/36me3 demethylase KDM4A, restored H3K36me3 levels and sensitivity to cytarabine. These findings establish alteration as a mechanism of resistance to DNA-damaging chemotherapy, consistent with a local loss of DDR, and identify a potential therapeutic strategy to target -mutant leukemias.

SETD2: a complex role in blood malignancy

“…n REFERENCES In this issue of Blood, Mar et al describe the effect of inactivating mutations of the histone methyltransferase (HMT) SETD2 in accelerating leukemia pathogenesis and conferring therapy resistance. 1 Mutations of epigenetic regulators are among the commonest lesions in malignancy. These include mutations of HMTs that modify histone tails protruding from the nucleosome.…”

“…Fluids with intermediate tonicities resulted in optimal changes that reduced the risk of vaso-occlusion. 1 O smosis is the movement of a neutral solvent across a semipermeable (red blood cell [RBC]) membrane from a less concentrated solution into a more concentrated one. This movement equalizes the concentration of solutes on each side of the membrane.…”

Loss of H3K36 Methyltransferase SETD2 Impairs V(D)J Recombination during Lymphoid Development

“…The complete loss of Setd2 is embryonic lethal at embryonic day 10.5 (E10.5)-E11.5 (Hu et al, 2010). Therefore, to study the role of Setd2 in normal and malignant hematopoiesis, we previously generated a conditional mouse model expressing Cre-recombinase under inducible (Mx1) or constitutive (Vav1) hematopoietic lineage-restricted promoters (Mar et al, 2017). The loss of Setd2 ablated H3K36me3 in hematopoietic tissues through excision of exon 3 of Setd2 ( Figure 1A).…”

SETD2 reduction adversely affects the development of mouse early embryos

“…4 Histone code, generated from these PTMs, is implicated in transcription, replication, repair, alternative splicing, and other chromatin-related cellular processes. [7][8][9] SETD2 was shown to determine chromatin integrity during transcription. 5,6 Functions of SETD2, from yeast to humans, are highly conserved.…”

“…5,6 Functions of SETD2, from yeast to humans, are highly conserved. [7][8][9] SETD2 was shown to determine chromatin integrity during transcription. 10 Pathogenic mutations in SETD2 were detected in cancers, including renal cell carcinomas, lung cancer, acute lymphoblastic leukemia, and central nervous system tumors.…”