In myeloid leukemia, nuclear reader YTHDC1 bound m6A-modified mRNA, forming nuclear condensates.
Major Finding: In myeloid leukemia, nuclear reader YTHDC1 bound m6A-modified mRNA, forming nuclear condensates.
Concept: Nuclear YTHDC1–m6A condensates protected mRNA targets, such as MYC, from PAXT-mediated degradation.
Impact: This study reveals how m6A- modified mRNA prevents differentiation and promotes survival in AML.
Messenger RNA can be posttranscriptionally regulated via modifications including N6-methyladenosine (m6A), and dysregulation of m6A modifications has been implicated in cancer. In myeloid leukemias, m6A has been shown to be required for tumorigenesis, but mechanisms by which m6A controls cell differentiation and survival are unknown. To investigate downstream effects of m6A, Cheng, Xie, and colleagues studied YTHDC1, a gene encoding a nuclear m6A reader. YTHDC1 scored as the top essential gene encoding a reader in a genome-wide CRISPR screen in acute myeloid leukemia (AML) cell lines. AML cell lines and primary patient samples expressed high levels of YTHDC1 mRNA and YTHDC1 protein, and knockdown of YTHDC1 inhibited cell proliferation, increased differentiation and apoptosis, and extended survival in a murine xenograft model. Given the intrinsically disordered regions within YTHDC1, recombinant EGFP–YTHDC1 was found to undergo droplet formation, which was enhanced in the presence of m6A-mRNA. Consistent with this observed liquid–liquid phase separation, endogenous EGFP-tagged YTHDC1 formed nuclear puncta and displayed liquid–liquid-like properties, providing evidence for YTHDC1-mediated condensate formation in AML cells. Nuclear YTHDC1–m6A condensates were essential for AML cell survival, as YTHDC1 mutants that were deficient in binding m6A were unable to form puncta and insufficient to rescue the decreased proliferation and increased differentiation observed upon YTHDC1 knockdown. RNA-sequencing analysis suggested that YTHDC1 promoted proliferation and inhibited myeloid differentiation, whereas protein–RNA interaction studies provided support for direct YTHDC1–m6A-mRNA binding and subsequent expression of mRNA targets, including MYC. The effects of YTHDC1 depletion on decreased proliferation and enhanced myeloid differentiation were partially rescued by MYC overexpression, highlighting MYC as an important functional target of YTHDC1. Nuclear YTHDC1–m6A condensates contributed to expression of m6A mRNA targets such as MYC by protecting mRNA from PAXT-driven nuclear exosome degradation. Together, this work describes a mechanism by which a nuclear reader promotes leukemogenesis via liquid–liquid phase separation and elucidates the functional role for m6A-modified mRNA in AML.
Cheng Y, Xie W, Pickering BF, Chu KL, Savino AM, Yang X, et al. N6-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation. Cancer Cell 2021 May 27 [Epub ahead of print].
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