Oncotarget

Research Papers:

Suppression of APC/CCdh1 has subtype specific biological effects in acute myeloid leukemia

Daniel Ewerth, Andrea Schmidts, Manuel Hein, Dominik Schnerch, Arunas Kvainickas, Christine Greil, Justus Duyster, Monika Engelhardt and Ralph Wäsch _

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Oncotarget. 2016; 7:48220-48230. https://doi.org/10.18632/oncotarget.10196

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Abstract

Daniel Ewerth1,2, Andrea Schmidts1, Manuel Hein1,3, Dominik Schnerch1, Arunas Kvainickas1,4, Christine Greil1, Justus Duyster1, Monika Engelhardt1, Ralph Wäsch1

1Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

2Faculty of Biology, University of Freiburg, Freiburg, Germany

3Present address: Department of Cardiology and Angiology II, University Heart Center Freiburg - Bad Krozingen, Faculty of Medicine, University of Freiburg, Bad Krozingen, Germany

4Present address: Center for Biological Systems Analysis, University of Freiburg, Freiburg, Germany

Correspondence to:

Ralph Wäsch, email: [email protected]

Keywords: anaphase-promoting complex, Cdh1, ubiquitin-ligase, acute myeloid leukemia, differentiation

Received: September 06, 2015     Accepted: June 09, 2016     Published: June 21, 2016

ABSTRACT

The E3 ubiquitin ligase and tumor suppressor APC/CCdh1 is crucial for cell cycle progression, development and differentiation in many cell types. However, little is known about the role of Cdh1 in hematopoiesis. Here we analyzed Cdh1 expression and function in malignant hematopoiesis. We found a significant decrease of Cdh1 in primary acute myeloid leukemia (AML) blasts compared to normal CD34+ cells. Thus, according to its important role in connecting cell cycle exit and differentiation, decreased expression of Cdh1 may be a mechanism contributing to the differentiation block in leukemogenesis. Indeed, knockdown (kd) of Cdh1 in HL-60 cell line (AML with maturation, FAB M2) led to less differentiated cells and a delay in PMA-induced differentiation. Acute promyelocytic leukemia (APL, FAB M3) is an AML subtype which is highly vulnerable to differentiation therapy with all-trans retinoic acid (ATRA). Accordingly, we found that APL is resistant to a Cdh1-kd mediated differentiation block. However, further depletion of Cdh1 in APL significantly reduced viability of leukemia cells upon ATRA-induced differentiation. Thus, low Cdh1 expression may be important in AML biology by contributing to the differentiation block and response to therapy depending on differences in the microenvironment and the additional genetic background.


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