E Protein Silencing by the Leukemogenic AML1-ETO Fusion Protein

Abstract

The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 15% of acute myeloid leukemia (AML) cases. This study shows that AML1-ETO, as well as ETO, inhibits transcriptional activation by E proteins through stable interactions that preclude recruitment of p300/CREB-binding protein (CBP) coactivators. These interactions are mediated by a conserved ETO TAF4 homology domain and a 17-amino acid p300/CBP and ETO target motif within AD1 activation domains of E proteins. In t(8;21) leukemic cells, very stable interactions between AML1-ETO and E proteins underlie a t(8;21) translocation-specific silencing of E protein function through an aberrant cofactor exchange mechanism. These studies identify E proteins as AML1-ETO targets whose dysregulation may be important for t(8;21) leukemogenesis, as well as an E protein silencing mechanism that is distinct from that associated with differentiation-inhibitory proteins.

Mtg16/Eto2 Contributes to Murine T-Cell Development

“…NHR2 forms strong homo-and hetero-oligomers with MTG family members (25,28,30). In fact, other MTG family members were the major associating proteins when MTGs or RUNX1-MTG8 was purified (25,48). Our analysis suggests that Mtg16 monomers retain function, and the observation that ⌬NHR1 and ⌬NICD impaired Mtg16 functions (Fig.…”

“…One of the interactions disrupted by the deletion of NHR1 is the interaction between this portion of Mtg16 and activation domain 1 (AD1) of HEB (48). Given that the Mtg16-null phenotype is similar to that of E2A-deficient mice (2, 4, 13, 22), we mined gene expression data from Mtg16-null LSK cells (M. Fischer, I. Moreno-Miralles, A.…”

“…The action of E proteins and Notch signaling are critical to T-cell development, and a potential role for Mtg16 in lymphopoiesis was further suggested by the identification of an association between MTGs and these pathways (9,14,19,38,41,48). Upon ligand binding, the Notch receptor is cleaved and the intracellular domain (ICD) of Notch moves to the nucleus and binds the transcription factor CBF1-Suppressor of Hairless-Lag1 (CSL) to activate transcription (26).…”

“…Likewise, Mtg16 associates with transcriptional activation domain 1 (AD1) in E proteins to impair E-protein-dependent transcription, and E2A instructs lymphoid development while inhibiting myelopoiesis (2,3,7,35,48). E2A-null mice have decreased numbers of thymocytes due to reduced lymphoidprimed multipotent progenitor (LMPP) and early thymocyte progenitor (ETP) production and impaired progression from the earliest CD4 Ϫ CD8 Ϫ CD44 ϩ CD25 Ϫ double-negative 1 (DN1) thymocytes to the subsequent CD4 Ϫ CD8 Ϫ CD44 ϩ CD25 ϩ DN2 thymocytes (2,4,13,24).…”

siRNA-mediated AML1/MTG8 depletion affects differentiation and proliferation-associated gene expression in t(8;21)-positive cell lines and primary AML blasts

“…Notably, introduction of AML1/MTG8 into one Aml1 allele resulted in a phenotype very similar to the one obtained by homozygous inactivation of Aml1, again suggesting that AML1/MTG8 acts as a transdominant repressor of AML1 functions (Yergeau et al, 1997). In addition, AML1/MTG8 binds and inhibits a variety of transcription factors relevant for myeloid differentiation Jakubowiak et al, 2000;Pabst et al, 2001;Puccetti et al, 2002;Vangala et al, 2003;Zhang et al, 2004).…”