ETO2–GLIS2 promotes megakaryocytic identify and self-renewal to promote AMKL.

  • Major finding: ETO2–GLIS2 promotes megakaryocytic identify and self-renewal to promote AMKL.

  • Mechanism: ETO2–GLIS2 binds enhancers to alter transcription, including upregulating ERG and downregulating GATA1.

  • Impact: Targeting the NHR2 domain may block ETO2–GLIS2 oligomerization to disrupt its oncogenic effects in AMKL.

Acute megakaryoblastic leukemia (AMKL) is characterized by the presence of fusion genes including ETO2–GLIS2, which is present in 20% to 30% of patients and associated with a poor prognosis. GLIS2 is a transcription factor that has been suggested to support the pluripotent stem cell state and contains DNA-binding zinc-finger domains that are retained in the ETO2–GLIS2 fusion, and ETO2 is a transcriptional cofactor involved in hematopoietic stem cell maintenance and differentiation. However, the molecular mechanism by which ETO2–GLIS2 promotes AMKL is not well defined, prompting Thirant, Ignacimouttou, Lopez, and colleagues to investigate its role in transformation. ETO2–GLIS2 expression in murine bone marrow progenitor cells promoted megakaryocytic differentiation, mediated by the GLIS2 moiety, and self-renewal, mediated by both the ETO2 and GLIS2 moieties. ETO2–GLIS2 bound directly to DNA through the GLIS2 moiety largely at H3K27ac-marked enhancers and superenhancers, and its occupancy also overlapped with the binding of known normal ETO2-interacting transcription factors including ETS (especially ERG), GATA, and RUNX proteins. ETO2–GLIS2 promoted gene transcription at de novo ETO2–GLIS2 loci while repressing transcription at ETO2 loci. Further, ETO2–GLIS2 was associated with increased expression of ERG target genes and reduced expression of GATA1, and ERG was required for the growth of ETO2–GLIS2-expressing AMKL cells. ETO proteins oligomerize through their NHR2 domain to recruit cofactors. Similarly, ETO2–GLIS2 interacted with both ETO2–GLIS2 and ETO2 through the NHR2 domain, and inhibition of the NHR2 domain downregulated ERG, upregulated GATA1, and reduced the growth of patient-derived ETO2–GLIS2-expressing AMKL cells in vitro and in vivo, indicating that ETO2–GLIS2 oligomerization and interaction with normal ETO2 transcriptional complexes is required for ETO2–GLIS2-mediated transcriptional regulation and transformation. In addition to elucidating the mechanism by which ETO2–GLIS2 promotes AMKL, these findings suggest that targeting ETO2–GLIS2 oligomerization may block its oncogenic effects.

Thirant C, Ignacimouttou C, Lopez CK, Diop M, Le Mouël L, Thiollier C, et al. ETO2-GLIS2 hijacks transcriptional complexes to drive cellular identity and self-renewal in pediatric acute megakaryoblastic leukemia. Cancer Cell 2017;31:452–65.

©2017 American Association for Cancer Research.
2017
American Association for Cancer Research.