MEIS2 Is an Oncogenic Partner in AML1-ETO-Positive AML

Naidu M Vegi; Josef Klappacher; Franz Oswald; Medhanie A Mulaw; Amit Mandoli; Verena N Thiel; Shiva Bamezai; Kristin Feder; Joost H A Martens; Vijay P S Rawat; Tamoghna Mandal; Leticia Quintanilla-Martinez; Karsten Spiekermann; Wolfgang Hiddemann; Konstanze Döhner; Hartmut Döhner; Hendrik G Stunnenberg; Michaela Feuring-Buske; Christian Buske

doi:10.1016/j.celrep.2016.05.094

MEIS2 Is an Oncogenic Partner in AML1-ETO-Positive AML

Cell Rep. 2016 Jul 12;16(2):498-507. doi: 10.1016/j.celrep.2016.05.094. Epub 2016 Jun 23.

Authors

Naidu M Vegi¹, Josef Klappacher¹, Franz Oswald², Medhanie A Mulaw¹, Amit Mandoli³, Verena N Thiel², Shiva Bamezai¹, Kristin Feder¹, Joost H A Martens³, Vijay P S Rawat¹, Tamoghna Mandal¹, Leticia Quintanilla-Martinez⁴, Karsten Spiekermann⁵, Wolfgang Hiddemann⁵, Konstanze Döhner⁶, Hartmut Döhner⁶, Hendrik G Stunnenberg³, Michaela Feuring-Buske⁶, Christian Buske⁷

Affiliations

¹ Institute of Experimental Cancer Research, CCC and University Hospital of Ulm, 89081 Ulm, Germany.
² Department of Internal Medicine I, Center for Internal Medicine, University Medical Center Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
³ Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500HB Nijmegen, the Netherlands.
⁴ Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, University Hospital Tübingen, Liebermeisterstrasse 8, 72076 Tübingen, Germany.
⁵ Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University (LMU), 81377 Munich, Germany.
⁶ Department of Internal Medicine III, University Hospital Ulm, 89081 Ulm, Germany.
⁷ Institute of Experimental Cancer Research, CCC and University Hospital of Ulm, 89081 Ulm, Germany; Core Facility Genomics, Medical Faculty Ulm, Ulm University, 89081 Ulm, Germany. Electronic address: [email protected].

PMID: 27346355
DOI: 10.1016/j.celrep.2016.05.094

Abstract

Homeobox genes are known to be key factors in leukemogenesis. Although the TALE family homeodomain factor Meis1 has been linked to malignancy, a role for MEIS2 is less clear. Here, we demonstrate that MEIS2 is expressed at high levels in patients with AML1-ETO-positive acute myeloid leukemia and that growth of AML1-ETO-positive leukemia depends on MEIS2 expression. In mice, MEIS2 collaborates with AML1-ETO to induce acute myeloid leukemia. MEIS2 binds strongly to the Runt domain of AML1-ETO, indicating a direct interaction between these transcription factors. High expression of MEIS2 impairs repressive DNA binding of AML1-ETO, inducing increased expression of genes such as the druggable proto-oncogene YES1. Collectively, these data describe a pivotal role for MEIS2 in AML1-ETO-induced leukemia.

MeSH terms

Animals
Carcinogenesis / genetics
Carcinogenesis / metabolism
Core Binding Factor Alpha 2 Subunit / genetics*
Core Binding Factor Alpha 2 Subunit / metabolism
Gene Expression
Gene Expression Regulation, Leukemic
HEK293 Cells
Homeodomain Proteins / genetics*
Homeodomain Proteins / metabolism
Humans
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / metabolism
Mice
Neoplasm Transplantation
Oncogene Proteins, Fusion / genetics*
Oncogene Proteins, Fusion / metabolism
Oncogenes
Promoter Regions, Genetic
Protein Binding
Proto-Oncogene Mas
Proto-Oncogene Proteins c-yes / genetics
Proto-Oncogene Proteins c-yes / metabolism
RUNX1 Translocation Partner 1 Protein / genetics*
RUNX1 Translocation Partner 1 Protein / metabolism
Transcription Factors / genetics*
Transcription Factors / metabolism

Substances

AML1-ETO fusion protein, human
Core Binding Factor Alpha 2 Subunit
Homeodomain Proteins
MAS1 protein, human
MEIS2 protein, human
Oncogene Proteins, Fusion
Proto-Oncogene Mas
RUNX1 Translocation Partner 1 Protein
Transcription Factors
Proto-Oncogene Proteins c-yes
YES1 protein, human