TY - JOUR
T1 - Autophagic degradation of the BCR-ABL oncoprotein and generation of antileukemic responses by arsenic trioxide
AU - Goussetis, Dennis J.
AU - Gounaris, Elias
AU - Wu, Edward J.
AU - Vakana, Eliza
AU - Sharma, Bhumika
AU - Bogyo, Matthew
AU - Altman, Jessica K.
AU - Platanias, Leonidas C.
PY - 2012/10/25
Y1 - 2012/10/25
N2 - We provide evidence that arsenic trioxide (As2O3) targets the BCR-ABL oncoprotein via a novel mechanism involving p62/ SQSTM1-mediated localization of the oncoprotein to the autolysosomes and subsequent degradation mediated by the protease cathepsin B. Our studies demonstrate that inhibitors of autophagy or cathepsin B activity and/or molecular targeting of p62/SQSTM1, Atg7, or cathepsin B result in partial reversal of the suppressive effects of AS2O3 on BCR-ABL expressing leukemic progenitors, including primitive leukemic precursors from chronic myelogenous leukemia (CML) patients. Altogether, these findings indicate that autophagic degradation of BCR-ABL is critical for the induction of the antileukemic effects of As2O3 and raise the potential for future therapeutic approaches to target BCR-ABL expressing cells by modulating elements of the autophagic machinery to promote BCR-ABL degradation.
AB - We provide evidence that arsenic trioxide (As2O3) targets the BCR-ABL oncoprotein via a novel mechanism involving p62/ SQSTM1-mediated localization of the oncoprotein to the autolysosomes and subsequent degradation mediated by the protease cathepsin B. Our studies demonstrate that inhibitors of autophagy or cathepsin B activity and/or molecular targeting of p62/SQSTM1, Atg7, or cathepsin B result in partial reversal of the suppressive effects of AS2O3 on BCR-ABL expressing leukemic progenitors, including primitive leukemic precursors from chronic myelogenous leukemia (CML) patients. Altogether, these findings indicate that autophagic degradation of BCR-ABL is critical for the induction of the antileukemic effects of As2O3 and raise the potential for future therapeutic approaches to target BCR-ABL expressing cells by modulating elements of the autophagic machinery to promote BCR-ABL degradation.
UR - http://www.scopus.com/inward/record.url?scp=84868526475&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84868526475&partnerID=8YFLogxK
U2 - 10.1182/blood-2012-01-402578
DO - 10.1182/blood-2012-01-402578
M3 - Article
C2 - 22898604
AN - SCOPUS:84868526475
SN - 0006-4971
VL - 120
SP - 3555
EP - 3562
JO - Blood
JF - Blood
IS - 17
ER -