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bioRxiv · 10.1101/2025.11.12.688028

Epigenetic silencing of transposable elements by IRF2BP2 is a selective dependency of myeloid leukemia

Xu, J.·Whittle, J.·Clayfield, L.·Lie-a-Ling, M.·Leddy, E. A.·Smith, D.·Sellers, R.·Deniz, O.·Lacaud, G.
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Abstract

Acute myeloid leukemia (AML) is a heterogeneous malignancy with limited curative treatment options. Transposable elements (TEs) are now recognized as key regulators of genome function, with aberrant activation implicated in cancer. However, their tumor-type-specific roles remain poorly characterized. Using single-cell Perturb-seq, we systematically screened for chromatin-associated regulators in primary AML patient cells to uncover dependencies required for leukemia cell viability. Our screen identified IRF2BP2 as an AML-selective dependency, functioning as a repressor of TE expression. Loss of IRF2BP2 induced differentiation, apoptosis, and impaired leukemic cell fitness, phenotypes linked to transcriptional activation of TEs, particularly evolutionarily young human endogenous retrovirus K (HERV-K). Mechanistically, IRF2BP2 cooperates with TRIM28 and DNMT1 to epigenetically silence TE expression. CRISPR-mediated activation of HERV-K/LTR5_Hs recapitulated the phenotypic effects of IRF2BP2 loss, while targeted re-silencing of HERV-K/LTR5_Hs partially rescued the effects, establishing a causal link between TE regulation and AML maintenance. Our findings highlight tumor-suppressive functions of TEs in leukemia and reveal IRF2BP2 as a key regulator of TE silencing in AML. Targeting the epigenetic machinery governing TE repression may represent a promising therapeutic avenue for differentiation-inducing and immunomodulatory strategies in AML.

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Xu, J., Whittle, J., Clayfield, L., Lie-a-Ling, M., Leddy, E. A., Smith, D., Sellers, R., Deniz, O., Lacaud, G.. 2025-11-13. Epigenetic silencing of transposable elements by IRF2BP2 is a selective dependency of myeloid leukemia. https://doi.org/10.1101/2025.11.12.688028

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