Arsenic but not all-trans retinoic acid overcomes the aberrant stem cell capacity of PML/RARalpha-positive leukemic stem cells.
OBJECTIVE
Stem cells play an important role in the pathogenesis and maintenance of most malignant tumors. Acute myeloid leukemia (AML) is a stem cell disease. The inefficient targeting of the leukemic stem cells (LSC) is considered responsible for relapse after the induction of complete hematologic remission (CR) in AML. Acute promyelocytic leukemia (APL) is a subtype of AML characterized by the t(15;17) translocation and expression of the PML/RARalpha fusion protein. Treatment of APL with all-trans retinoic acid (ATRA) induces CR, but not molecular remission (CMR), because the fusion transcript remains detectable, followed by relapse within a few months. Arsenic induces high rates of CR and CMR followed by a long relapse-free survival (RFS). Here we compared the effects of ATRA and arsenic on PML/RARalpha-positive stem cell compartments.


METHODS
As models for the PML/RARalpha-positive LSC we used: (i) Sca1+/lin- murine HSC retrovirally transduced with PML/RARalpha; (ii) LSC from mice with PML/RARalpha-positive leukemia; (iii) the side population of the APL cell line NB4.


RESULTS
In contrast to ATRA, arsenic abolishes the aberrant stem cell capacity of PML/RARalpha-positive stem cells. Arsenic had no apparent influence on the proliferation of PML/RARalpha-positive stem cells, whereas ATRA greatly increased the proliferation of these cells. Furthermore ATRA induces proliferation of APL-derived stem cells, whereas arsenic inhibits their growth.


CONCLUSIONS
Taken together our data suggest a relationship between the capacity of a compound to target the leukemia-initiating cell and its ability to induce long relapse-free survival. These data strongly support the importance of efficient LSC-targeting for the outcome of patients with leukemia.
Zheng
Xiaomin
X
Laboratory of Tumor Stem Cell Biology, Department of Hematology, J.W. Goethe University, Frankfurt, Germany.
Seshire
Anita
A
Rüster
Brigitte
B
Bug
Gesine
G
Beissert
Tim
T
Puccetti
Elena
E
Hoelzer
Dieter
D
Henschler
Reinhard
R
Ruthardt
Martin
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D000067696:Ataxin-1; D000067528:Ataxins; D014408:Biomarkers, Tumor / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000032:analysis; D009687:Nuclear Proteins / Q000032:analysis; D015514:Oncogene Proteins, Fusion / Q000032:analysis / Q000502:physiology; D010087:Oxides / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D014212:Tretinoin / Q000008:administration & dosage / Q000494:pharmacology; D014410:Tumor Stem Cell Assay
C000593749:ATXN1 protein, human; D000970:Antineoplastic Agents; D001152:Arsenicals; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D014408:Biomarkers, Tumor; D006131:Growth Inhibitors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D010087:Oxides; D011993:Recombinant Fusion Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D000077237:Arsenic Trioxide