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Cancer Discov. 2018 Nov;8(11):1376-1389. doi: 10.1158/2159-8290.CD-17-0841. Epub 2018 Aug 16.

Targeting the MTF2-MDM2 Axis Sensitizes Refractory Acute Myeloid Leukemia to Chemotherapy.

Author information

1
The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
2
Ottawa Institute of Systems Biology, Ottawa, Ontario, Canada.
3
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
4
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
5
Ottawa Bioinformatics Core Facility, The Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
6
Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, Illinois.
7
Clinical Epidemiology Methods Centre, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
8
Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
9
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
10
The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. wstanford@ohri.ca cito@ohri.ca.
#
Contributed equally

Abstract

Deep sequencing has revealed that epigenetic modifiers are the most mutated genes in acute myeloid leukemia (AML). Thus, elucidating epigenetic dysregulation in AML is crucial to understand disease mechanisms. Here, we demonstrate that metal response element binding transcription factor 2/polycomblike 2 (MTF2/PCL2) plays a fundamental role in the polycomb repressive complex 2 (PRC2) and that its loss elicits an altered epigenetic state underlying refractory AML. Unbiased systems analyses identified the loss of MTF2-PRC2 repression of MDM2 as central to, and therefore a biomarker for, refractory AML. Thus, immature MTF2-deficient CD34+CD38- cells overexpress MDM2, thereby inhibiting p53 that leads to chemoresistance due to defects in cell-cycle regulation and apoptosis. Targeting this dysregulated signaling pathway by MTF2 overexpression or MDM2 inhibitors sensitized refractory patient leukemic cells to induction chemotherapeutics and prevented relapse in AML patient-derived xenograft mice. Therefore, we have uncovered a direct epigenetic mechanism by which MTF2 functions as a tumor suppressor required for AML chemotherapeutic sensitivity and identified a potential therapeutic strategy to treat refractory AML.Significance: MTF2 deficiency predicts refractory AML at diagnosis. MTF2 represses MDM2 in hematopoietic cells and its loss in AML results in chemoresistance. Inhibiting p53 degradation by overexpressing MTF2 in vitro or by using MDM2 inhibitors in vivo sensitizes MTF2-deficient refractory AML cells to a standard induction-chemotherapy regimen. Cancer Discov; 8(11); 1376-89. ©2018 AACR. See related commentary by Duy and Melnick, p. 1348 This article is highlighted in the In This Issue feature, p. 1333.

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