Deacetylase inhibitors modulate proliferation and self-renewal properties of leukemic stem and progenitor cells.
Acute myeloid leukemia (AML) is a highly malignant disease that is not curable in the majority of patients. Numerous non-random genetic abnormalities are known, among which several translocations such as PLZF/RARα or AML1/ETO are known to aberrantly recruit histone deacetylases. Deacetylase inhibitors (DACi) are promising drugs leading to growth inhibition, cell cycle arrest, premature senescence and apoptosis in malignant cells. It is believed that DACi may have clinical efficacy by eradicating the most primitive population of leukemic stem and progenitor cells, possibly by interfering with self-renewal. The aim of the study was to investigate the effects of DACi on leukemic stem and progenitor cells using murine transduction-transplantation models of hematopoietic cells harboring the leukemia-associated fusion proteins (LAFP) PLZF/RARα or a truncated AML1/ETO protein (AML1/ETO exon 9). We show that the self-renewal and short-term repopulation capacity of AML1/ETO- or PLZF/RARα-expressing Sca1+/lin- stem and progenitor cells are profoundly inhibited by clinically applicable concentrations of the DACi dacinostat and vorinostat. To further investigate the mechanisms underlying these effects, we examined the impact of DACi on the transcription factor c-MYC and the Polycomb group protein BMI1, which are induced by LAFP and involved in leukemic transformation. In AML1/ETO or PLZF/RARα-positive 32D cells, DACi-mediated antiproliferative effects were associated with downregulation of BMI1 and c-MYC protein levels. Similar effects were demonstrated in primary samples of cytogenetically defined high-risk AML patients. In conclusion, DACi may be effective as maintenance therapy by negatively interfering with signaling pathways that control survival and proliferation of leukemic stem and progenitor cells.
Department of Medicine II, Hematology and Oncology, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.
Annette
A
Romanski
Kerstin
K
Schwarz
Maren
M
Keller
Sarah
S
Wietbrauk
Anja
A
Vogel
Jessica
J
Roos
Claudia
C
Oancea
Boris
B
Brill
Oliver H
OH
Krämer
Hubert
H
Serve
Martin
M
Ruthardt
Gesine
G
Bug
D000818:Animals; D015153:Blotting, Western; D003114:Colony-Forming Units Assay; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077337:Vorinostat
C489421:Bmi1 protein, mouse; D050676:Core Binding Factor Alpha 2 Subunit; D017931:DNA Primers; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C489428:Myc protein, mouse; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; C493726:Runx1 protein, mouse; D000077337:Vorinostat; D063150:Polycomb Repressive Complex 1; D006655:Histone Deacetylases