Definition of a small core transcriptional circuit regulated by AML1-ETO.

Transcription factors regulate gene networks controlling normal hematopoiesis and are frequently deregulated in acute myeloid leukemia (AML). Critical to our understanding of the mechanism of cellular transformation by oncogenic transcription factors is the ability to define their direct gene targets. However, gene network cascades can change within minutes to hours, making it difficult to distinguish direct from secondary or compensatory transcriptional changes by traditional methodologies. To overcome this limitation, we devised cell models in which the AML1-ETO protein could be quickly degraded upon addition of a small molecule. The rapid kinetics of AML1-ETO removal, when combined with analysis of transcriptional output by nascent transcript analysis and genome-wide AML1-ETO binding by CUT&RUN, enabled the identification of direct gene targets that constitute a core AML1-ETO regulatory network. Moreover, derepression of this gene network was associated with RUNX1 DNA binding and triggered a transcription cascade ultimately resulting in myeloid differentiation.

Stengel KR ，Ellis JD ，Spielman CL ，Bomber ML ，Hiebert SW ... -  《-》

PLCG1 is required for AML1-ETO leukemia stem cell self-renewal.

In an effort to identify novel drugs targeting fusion-oncogene-induced acute myeloid leukemia (AML), we performed high-resolution proteomic analysis. In AML1-ETO (AE)-driven AML, we uncovered a deregulation of phospholipase C (PLC) signaling. We identified PLCgamma 1 (PLCG1) as a specific target of the AE fusion protein that is induced after AE binding to intergenic regulatory DNA elements. Genetic inactivation of PLCG1 in murine and human AML inhibited AML1-ETO dependent self-renewal programs, leukemic proliferation, and leukemia maintenance in vivo. In contrast, PLCG1 was dispensable for normal hematopoietic stem and progenitor cell function. These findings are extended to and confirmed by pharmacologic perturbation of Ca++-signaling in AML1-ETO AML cells, indicating that the PLCG1 pathway poses an important therapeutic target for AML1-ETO+ leukemic stem cells.

Schnoeder TM ，Schwarzer A ，Jayavelu AK ，Hsu CJ ，Kirkpatrick J ，Döhner K ，Perner F ，Eifert T ，Huber N ，Arreba-Tutusaus P ，Dolnik A ，Assi SA ，Nafria M ，Jiang L ，Dai YT ，Chen Z ，Chen SJ ，Kellaway SG ，Ptasinska A ，Ng ES ，Stanley EG ，Elefanty AG ，Buschbeck M ，Bierhoff H ，Brodt S ，Matziolis G ，Fischer KD ，Hochhaus A ，Chen CW ，Heidenreich O ，Mann M ，Lane SW ，Bullinger L ，Ori A ，von Eyss B ，Bonifer C ，Heidel FH ... -  《-》

An AML1-ETO/miR-29b-1 regulatory circuit modulates phenotypic properties of acute myeloid leukemia cells.

Zaidi SK ，Perez AW ，White ES ，Lian JB ，Stein JL ，Stein GS ... -  《Oncotarget》

The Hematopoietic Transcription Factors RUNX1 and ERG Prevent AML1-ETO Oncogene Overexpression and Onset of the Apoptosis Program in t(8;21) AMLs.

The t(8;21) acute myeloid leukemia (AML)-associated oncoprotein AML1-ETO disrupts normal hematopoietic differentiation. Here, we have investigated its effects on the transcriptome and epigenome in t(8,21) patient cells. AML1-ETO binding was found at promoter regions of active genes with high levels of histone acetylation but also at distal elements characterized by low acetylation levels and binding of the hematopoietic transcription factors LYL1 and LMO2. In contrast, ERG, FLI1, TAL1, and RUNX1 bind at all AML1-ETO-occupied regulatory regions, including those of the AML1-ETO gene itself, suggesting their involvement in regulating AML1-ETO expression levels. While expression of AML1-ETO in myeloid differentiated induced pluripotent stem cells (iPSCs) induces leukemic characteristics, overexpression increases cell death. We find that expression of wild-type transcription factors RUNX1 and ERG in AML is required to prevent this oncogene overexpression. Together our results show that the interplay of the epigenome and transcription factors prevents apoptosis in t(8;21) AML cells.

Mandoli A ，Singh AA ，Prange KHM ，Tijchon E ，Oerlemans M ，Dirks R ，Ter Huurne M ，Wierenga ATJ ，Janssen-Megens EM ，Berentsen K ，Sharifi N ，Kim B ，Matarese F ，Nguyen LN ，Hubner NC ，Rao NA ，van den Akker E ，Altucci L ，Vellenga E ，Stunnenberg HG ，Martens JHA ... -  《Cell Reports》

Chromatin modifications induced by the AML1-ETO fusion protein reversibly silence its genomic targets through AML1 and Sp1 binding motifs.

Maiques-Diaz A ，Chou FS ，Wunderlich M ，Gómez-López G ，Jacinto FV ，Rodriguez-Perales S ，Larrayoz MJ ，Calasanz MJ ，Mulloy JC ，Cigudosa JC ，Alvarez S ... -  《-》