TY - JOUR
T1 - The Hematopoietic Transcription Factors RUNX1 and ERG Prevent AML1-ETO Oncogene Overexpression and Onset of the Apoptosis Program in t(8;21) AMLs
AU - Mandoli, Amit
AU - Singh, Abhishek A.
AU - Prange, Koen H. M.
AU - Tijchon, Esther
AU - Oerlemans, Marjolein
AU - Dirks, Rene
AU - Ter Huurne, Menno
AU - Wierenga, Albertus T. J.
AU - Janssen-Megens, Eva M.
AU - Berentsen, Kim
AU - Sharifi, Nilofar
AU - Kim, Bowon
AU - Matarese, Filomena
AU - Nguyen, Luan N.
AU - Hubner, Nina C.
AU - Rao, Nagesha A.
AU - van den Akker, Emile
AU - Altucci, Lucia
AU - Vellenga, Edo
AU - Stunnenberg, Hendrik G.
AU - Martens, Joost H. A.
PY - 2016/11/15
Y1 - 2016/11/15
N2 - 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.
AB - 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.
KW - ACUTE MYELOID-LEUKEMIA
KW - PLURIPOTENT STEM-CELLS
KW - SELF-RENEWAL
KW - GENOME-WIDE
KW - GRANULOCYTIC DIFFERENTIATION
KW - DEFINITIVE HEMATOPOIESIS
KW - GENE-EXPRESSION
KW - HDAC INHIBITION
KW - HISTONE H4
KW - AML1/ETO
U2 - 10.1016/j.celrep.2016.08.082
DO - 10.1016/j.celrep.2016.08.082
M3 - Article
C2 - 27851970
SN - 2211-1247
VL - 17
SP - 2087
EP - 2100
JO - Cell reports
JF - Cell reports
IS - 8
ER -