BCR-ABL1-induced leukemogenesis and autophagic targeting by arsenic trioxide.
We have recently shown that arsenic trioxide (As 2O 3) is a potent inducer of autophagic degradation of the BCR-ABL1 oncoprotein, which is the cause of chronic myeloid leukemia (CML) and Ph+ acute lymphoid leukemia (Ph+ ALL). Our recently published work has shown that pharmacological inhibition of autophagy or molecularly targeting of elements of the autophagic machinery partially reverses the suppressive effects of As 2O 3 on primitive leukemic precursors from CML patients. Altogether, our studies have provided direct evidence that arsenic-induced, autophagy-mediated, degradation of BCR-ABL1 is an important mechanism for the generation of the effects of As 2O 3 on BCR-ABL1 transformed leukemic progenitors. These studies raise the potential of future clinical-translational efforts employing combinations of arsenic trioxide with autophagy-modulating agents to promote elimination of early leukemic progenitors and, possibly, leukemia-initiating stem cells.
Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Dennis J
DJ
Goussetis
Elias
E
Gounaris
Leonidas C
LC
Platanias
D000970:Antineoplastic Agents / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010087:Oxides / Q000633:toxicity*; D057170:Translational Research, Biomedical
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D016044:Fusion Proteins, bcr-abl; D000077237:Arsenic Trioxide