Histone Deacetylase Inhibitors Target the Leukemic Microenvironment by Enhancing a Nherf1-Protein Phosphatase 1α-TAZ Signaling Pathway in Osteoblasts.
Disrupting the protective signals provided by the bone marrow microenvironment will be critical for more effective combination drug therapies for acute myeloid leukemia (AML). Cells of the osteoblast lineage that reside in the endosteal niche have been implicated in promoting survival of AML cells. Here, we investigated how to prevent this protective interaction. We previously showed that SDF-1, a chemokine abundant in the bone marrow, induces apoptosis of AML cells, unless the leukemic cells receive protective signals provided by differentiating osteoblasts (8, 10). We now identify a novel signaling pathway in differentiating osteoblasts that can be manipulated to disrupt the osteoblast-mediated protection of AML cells. Treating differentiating osteoblasts with histone deacetylase inhibitors (HDACi) abrogated their ability to protect co-cultured AML cells from SDF-1-induced apoptosis. HDACi prominently up-regulated expression of the Nherf1 scaffold protein, which played a major role in preventing osteoblast-mediated protection of AML cells. Protein phosphatase-1α (PP1α) was identified as a novel Nherf1 interacting protein that acts as the downstream mediator of this response by promoting nuclear localization of the TAZ transcriptional modulator. Moreover, independent activation of either PP1α or TAZ was sufficient to prevent osteoblast-mediated protection of AML cells even in the absence of HDACi. Together, these results indicate that HDACi target the AML microenvironment by enhancing activation of the Nherf1-PP1α-TAZ pathway in osteoblasts. Selective drug targeting of this osteoblast signaling pathway may improve treatments of AML by rendering leukemic cells in the bone marrow more susceptible to apoptosis.
From the Departments of Immunology.
Kimberly N
KN
Kremer
Orthopedic Surgery.
Amel
A
Dudakovic
the Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, Maryland 21287.
Allan D
AD
Hess
the Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, Maryland 21287.
B Douglas
BD
Smith
the Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, Maryland 21287.
Judith E
JE
Karp
Oncology and Molecular Pharmacology & Experimental Therapeutics and.
Scott H
SH
Kaufmann
Orthopedic Surgery, the Center of Regenerative Medicine, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota 55905 and.
Jennifer J
JJ
Westendorf
Orthopedic Surgery, the Center of Regenerative Medicine, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota 55905 and.
Andre J
AJ
van Wijnen
From the Departments of Immunology, hedin.karen@mayo.edu.
Karen E
KE
Hedin
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D001853:Bone Marrow / Q000378:metabolism; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D018920:Coculture Techniques; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D059016:Tumor Microenvironment
C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D056572:Histone Deacetylase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D017923:Sodium-Hydrogen Exchangers; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; C093376:sodium-hydrogen exchanger regulatory factor; D054645:Protein Phosphatase 1
AML; CXCR4; Nherf1; SDF-1; TAZ; apoptosis; histone deacetylase inhibitor (HDAC inhibitor) (HDI); leukemia; osteoblast; phosphoprotein phosphatase 1 (PP1)