Oncotarget

Research Papers:

Discovery and functional implications of a miR-29b-1/miR-29a cluster polymorphism in acute myeloid leukemia

Apollinaire Ngankeu, Parvathi Ranganathan, Violaine Havelange, Deedra Nicolet, Stefano Volinia, Bayard L. Powell, Jonathan E. Kolitz, Geoffrey L. Uy, Richard M. Stone, Steven M. Kornblau, Michael Andreeff, Carlo M. Croce, Clara D. Bloomfield, Ramiro Garzon _

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Oncotarget. 2018; 9:4354-4365. https://doi.org/10.18632/oncotarget.23150

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Abstract

Apollinaire Ngankeu1, Parvathi Ranganathan1, Violaine Havelange3, Deedra Nicolet4,11, Stefano Volinia5, Bayard L. Powell6, Jonathan E. Kolitz7, Geoffrey L. Uy8, Richard M. Stone9, Steven M. Kornblau10, Michael Andreeff10, Carlo M. Croce2, Clara D. Bloomfield1 and Ramiro Garzon1

1Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA

2Department of Molecular Virology, Immunology and Medical Genetics at The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

3Hematological Department, Cliniques Universitaires Saint-Luc, Brussels, Belgium

4Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

5Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy

6The Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, USA

7North Shore Cancer Institute, Lake Success, NY, USA

8Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA

9Dana-Farber Cancer Institute, Harvard University, Boston, MA, USA

10Department of Leukemia, MD Anderson Cancer Center, Texas State University, Houston, TX, USA

11Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN, USA

Correspondence to:

Ramiro Garzon, email: Ramiro.garzon@osumc.edu

Keywords: polymorphism; miR-29b-1/miR-29a cluster; AML

Received: June 03, 2017     Accepted: October 25, 2017     Published: December 12, 2017

ABSTRACT

We previously reported that microRNA (miR)-29b is down-regulated and has a tumor suppressor role in acute myeloid leukemia (AML). However, little is known about the mechanisms responsible for miR-29b expression downregulation in AML. In this work we screened for mutations that could affect miR-29b expression. Using Sanger sequencing, we identified a germline thymidine (T) base deletion within the miR-29b-1/miR-29a cluster precursor in 16% of AML patients. Remarkably we found a significant enrichment for the presence of the miR-29 polymorphism in core binding factor (CBF) newly diagnosed AML patients (n = 61/303; 20%) with respect to age, sex and race matched controls (n = 43/402:11%, P < 0.01). Mechanistically, this polymorphism affects the expression ratio of mature miR-29b and miR-29a by dampening the processing of miR-29a. RNA immunoprecipitation assays showed reduced DROSHA binding capacity to the polymorphism with respect to the controls. Finally, we showed that this polymorphism negatively impacts the ability of miR-29b-1/miR-29a cluster to target MCL-1 and CDK6, both known miR-29 targets.


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