Histone deacetylase inhibitors reduce differentiating osteoblastmediated protection of acute myeloid leukemia cells from cytarabine

Rosalie M. Sterner, Kimberly N. Kremer, Aref Al-Kali, Mrinal M Patnaik, Naseema Gangat, Mark R Litzow, Scott H Kaufmann, Jennifer J Westendorf, Andre J van Wijnen, Karen Elaine Hedin

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)94569-94579
Number of pages11
JournalOncotarget
Volume8
Issue number55
DOIs
StatePublished - Nov 1 2017

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Histone Deacetylase Inhibitors
Cytarabine
Myeloid Cells
Acute Myeloid Leukemia
Osteoblasts
Bone Marrow
Recurrence
Drug Therapy
Coculture Techniques
Bone Marrow Cells
Cell Survival
Apoptosis
Gene Expression

Keywords

  • AML
  • HDACi
  • Osteoblast
  • Panobinostat
  • Vorinostat

ASJC Scopus subject areas

  • Oncology

Cite this

Histone deacetylase inhibitors reduce differentiating osteoblastmediated protection of acute myeloid leukemia cells from cytarabine. / Sterner, Rosalie M.; Kremer, Kimberly N.; Al-Kali, Aref; Patnaik, Mrinal M; Gangat, Naseema; Litzow, Mark R; Kaufmann, Scott H; Westendorf, Jennifer J; van Wijnen, Andre J; Hedin, Karen Elaine.

In: Oncotarget, Vol. 8, No. 55, 01.11.2017, p. 94569-94579.

Research output: Contribution to journalArticle

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