The leukemia-associated transcription repressor AML1/MDS1/EVI1 requires CtBP to induce abnormal growth and differentiation of murine hematopoietic cells

Abstract

The leukemia-associated fusion gene AML1/MDS1/ EVI1 (AME) encodes a chimeric transcription factor that results from the (3;21)(q26;q22) translocation. This translocation is observed in patients with therapy-related myelodysplastic syndrome (MDS), with chronic myelogenous leukemia during the blast crisis (CML-BC), and with de novo or therapy-related acute myeloid leukemia (AML). AME is obtained by in-frame fusion of the AML1 and MDS1/EVI1 genes. We have previously shown that AME is a transcriptional repressor that induces leukemia in mice. In order to elucidate the role of AME in leukemic transformation, we investigated the interaction of AME with the transcription co-regulator CtBP1 and with members of the histone deacetylase (HDAC) family. In this report, we show that AME physically interacts in vivo with CtBP1 and HDAC1 and that these co-repressors require distinct regions of AME for interaction. By using reporter gene assays, we demonstrate that AME represses gene transcription by CtBP1-dependent and CtBP1-independent mechanisms. Finally, we show that the interaction between AME and CtBP1 is biologically important and is necessary for growth upregulation and abnormal di erentiation of the murine hematopoietic precursor cell line 32Dc13 and of murine bone marrow progenitors.

Both AML1 and EVI1 oncogenic components are required for the cooperation of AML1/MDS1/EVI1 with BCR/ABL in the induction of acute myelogenous leukemia in mice

“…On the other hand, AME, like EVI1, can abrogate TGFb signaling by interacting with and inhibiting Smad3 and can also stimulate c-fos promoter transactivation and increase AP-1 activity (Tanaka et al, 1995;Kurokawa et al, 1998). It has also been shown recently that AME, similar to EVI1, can interact with the corepressor CtBP1 (Izutsu et al, 2002;Senyuk et al, 2002). In addition, the fusion between the AML1 and EVI1 oncogenes may also generate fusion-specific functions.…”

Two Nonconsensus Sites in the Epstein-Barr Virus Oncoprotein EBNA3A Cooperate to Bind the Co-repressor Carboxyl-terminal-binding Protein (CtBP)

“…The AML1/MDS/EVI1 fusion gene expressed in various hematological malignancies encodes a protein that binds CtBP. The interaction between this oncoprotein and CtBP is also biologically important and appears to be involved in growth deregulation and abnormal differentiation of murine hematopoietic cells (45). The similarities between EVI1 and EBNA3A and EBNA3C are quite striking and will be studied further.…”

EVI1 Abrogates Interferon-α Response by Selectively Blocking PML Induction

“…Cell Culture and Murine BM Progenitors Culture-The maintenance, transfection, and culture of the retroviral producer cell line Phoenix (ATCC) have been reported (22,41). The infection, selection, culture, and differentiation of murine BM progenitors infected with the empty MSCV retrovirus or MSCV-HA-EVI1 were carried out as described (41).…”

“…The infection, selection, culture, and differentiation of murine BM progenitors infected with the empty MSCV retrovirus or MSCV-HA-EVI1 were carried out as described (41). EVI1-expressing SiHa stable lines were generated by calcium phosphate transfection with either the pCMV vector (vector-SiHa) or pCMVFlag-EVI1 (EVI1-SiHa) and selection with neomycin.…”