MPP8 Silences LINE-1 Retrotransposons to Promote Acute Myeloid Leukemia

LINE-1 retrotransposons are autonomously mobile transposable elements that can cause disease, including cancer, via insertional mutagenesis. For unknown reasons, evidence of LINE-1 retrotransposition events is common in solid tumors but less so in myeloid cancers. Using a CRISPR–Cas9-based knockout screen targeting epigenetic regulators, Gu, Liu, and colleagues discovered that MPP8 (also known as MPHOSPH8), encoding a chromodomain-containing protein that is a component of the retrotransposon-suppressing human silencing hub (HUSH) complex, was a key dependency of human acute myeloid leukemia (AML) cells in vitro. Further, mice xenotransplanted with MPP8-deficient AML cells had significantly longer survival and lower leukemia burden than mice xenotransplanted with control AML cells. Additional in vivo experiments showed that normal hematopoiesis did not require MPP8, whereas Mpp8 knockout in a mouse model of AML1–ETO- or MLL–AF9-driven AML resulted in substantially reduced AML mortality and leukemia burden. Mechanistically, loss of MPP8 in human AML cells in vitro led to reactivation of normally repressed LINE-1 retrotransposons, whereas blocking LINE-1 retrotransposition restored cell growth in MPP8-deficient AML cells, both consistent with MPP8's function as the chromatin reader of the HUSH complex. In patient samples, lower LINE-1 expression was associated with poorer prognosis, and the presence of AML driver mutations in genetically engineered mouse models caused LINE-1 downregulation, suggesting that LINE-1 activity may be tumor suppressive in AML and that AML-inducing oncogenic mutations promote LINE-1 silencing. Indeed, CRISPR–Cas9-based activation of endogenous LINE-1 retrotransposons reduced leukemia cell growthin vitro and in xenotransplants. Further investigation of the mechanism underlying the dependency of AML cells on MPP8 revealed that HUSH complex–mediated silencing of LINE-1 retrotransposons was essential to prevent DNA damage and the resulting cell-cycle exit, a known sensitivity of myeloid leukemia cells. In summary, this work reveals MPP8 as a core factor promoting AML that acts by suppressing LINE-1 transcription to promote genome stability in leukemia cells.

Gu Z, Liu Y, Zhang Y, Cao H, Lyu J, Wang X, et al. Silencing of LINE-1 retrotransposons is a selective dependency of myeloid leukemia. Nat Genet 2021;53:672–82.

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