Histone deacetylase inhibitors reduce differentiating osteoblast-mediated protection of acute myeloid leukemia cells from cytarabine
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Rosalie M. Sterner1,2, Kimberly N. Kremer2, Aref Al-Kali3, Mrinal M. Patnaik3, Naseema Gangat3, Mark R. Litzow3, Scott H. Kaufmann3,4, Jennifer J. Westendorf5, Andre J. van Wijnen5 and Karen E. Hedin2
1Mayo Clinic Medical Scientist Training Program, Mayo Clinic College of Medicine and Science, Rochester, Minnesota 55905, USA
2Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota 55905, USA
3Division of Hematology and Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota 55905, USA
4Department of Oncology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota 55905, USA
5Department of Orthopedic Surgery and Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota 55905, USA
Karen E. Hedin email: email@example.com
Keywords: AML, osteoblast, HDACi, vorinostat, panobinostat
Abbreviations: AML, acute myeloid leukemia; HADCi, histone deacetylase inhibitors; BMSC, bone marrow-derived mesenchymal stromal/stem cells; v/v, volume/volume
Received: May 18, 2017 Accepted: September 15, 2017 Published: October 10, 2017
The bone marrow microenvironment protects acute myeloid leukemia (AML) cells during chemotherapy and is a major factor in relapse. Here, we examined which type(s) of bone marrow cells are responsible for the relapse of AML following treatment with cytarabine (Ara-C), and we identified a means to inhibit this protection. To determine the protective cell type(s), AML cells were treated with Ara-C, and AML cell survival in the presence or absence of osteoblast lineage cells was assessed. Cultured AML cells and patient bone marrow isolates were each significantly protected from Ara-C-induced apoptosis by co-culture with differentiating osteoblasts. Moreover, pretreating differentiating osteoblasts with the histone deacetylase inhibitors (HDACi) vorinostat and panobinostat abrogated the ability of the differentiating osteoblasts to protect AML cells. Together, our results indicate that differentiating osteoblasts have the potential to promote residual AML in the bone marrow following standard chemotherapy and act via a mechanism requiring HDACi-sensitive gene expression. Using HDACi to target the leukemic microenvironment in combination with Ara-C could potentially improve treatment of AML. Moreover, other strategies for manipulating bone marrow osteoblasts may also help eradicate AML cells and reduce relapse.
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