2001 – HUSHING LINE-1 RETROTRANSPOSITION IS AN EPIGENETIC LIABILITY OF MYELOID LEUKEMIAS

Abstract

Hijacked epigenetic machinery is a hallmark of acute myeloid leukemia (AML), whereas dysregulated epigenetics also creates selective and targetable dependencies. The identification of leukemia-selective dependencies provides new knowledge in AML pathogenesis, resulting in therapeutic strategies targeting several epigenetic regulators. These strategies rely mainly on interfering with the activity of chromatin-interacting domains, highlighting the importance of understanding protein domains in cancer pathobiology. However, a comprehensive survey of epigenetic dependencies of human leukemias by a domain-based functional interrogation has been lacking. We developed a CRISPR screen system using domain-based sgRNAs targeting human chromatin regulators, and identified MPHOSPH8 (or MPP8), a methyl-H3K9-binding component of the HUSH complex, as a selective epigenetic dependency of AML cells. HUSH mediates the epigenetic silencing of LINE-1 (or L1) retrotransposons, the only autonomously mobile DNA elements in humans. While dispensable for normal hematopoiesis, MPP8 KO inhibits AML initiation and maintenance by reactivating L1 retrotransposons. Activation of endogenous or ectopic L1s phenocopied MPP8 loss, whereas blocking L1 retrotransposition abrogated MPP8-deficiency-induced phenotypes. Reactivated L1 retrotransposition increased DNA damage, activated cyclin-dependent kinase inhibitor p21, and induced AML differentiation. Furthermore, expression of AML oncogenes led to suppression of L1s in human and mouse HSPCs. Enhanced L1 suppression in human AML cells is associated with therapy resistance and poor prognosis. Hence, while retrotransposons are historically recognized as sources of genetic instability and somatic mutations to promote cancer development, we uncover an unexpected tumor-suppressive role for L1 retrotransposons as an epigenetic liability in myeloid leukemias.