title: The core autophagy protein ATG4B is a potential biomarker and therapeutic target in CML stem/progenitor cells.
abstract: Previous studies demonstrated that imatinib mesylate (IM) induces autophagy in chronic myeloid leukemia (CML) and that this process is critical to cell survival upon therapy. However, it is not known if the autophagic process differs at basal levels between CML patients and healthy individuals and if pretreatment CML cells harbor unique autophagy characteristics that could predict patients' clinical outcomes. We now demonstrate that several key autophagy genes are differentially expressed in CD34(+) hematopoietic stem/progenitor cells, with the highest transcript levels detected for ATG4B, and that the transcript and protein expression levels of ATG4 family members, ATG5 and BECLIN-1 are significantly increased in CD34(+) cells from chronic-phase CML patients (P < .05). Importantly, ATG4B is differentially expressed in pretreatment CML stem/progenitor cells from subsequent IM responders vs IM nonresponders (P < .05). Knockdown of ATG4B suppresses autophagy, impairs the survival of CML stem/progenitor cells and sensitizes them to IM treatment. Moreover, deregulated expression of ATG4B in CD34(+) CML cells inversely correlates with transcript levels of miR-34a, and ATG4B is shown to be a direct target of miR-34a. This study identifies ATG4B as a potential biomarker for predicting therapeutic response in treatment-naïve CML stem/progenitor cells and uncovers ATG4B as a possible drug target in these cells.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Medical Genetics and.
authors.forename: Katharina
authors.initials: K
authors.lastname: Rothe
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Medicine, University of British Columbia, Vancouver, BC, Canada;
authors.forename: Hanyang
authors.initials: H
authors.lastname: Lin
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Kevin B L
authors.initials: KB
authors.lastname: Lin
authors.affiliation: Genome Sciences Centre and.
authors.forename: Amy
authors.initials: A
authors.lastname: Leung
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Hui Mi
authors.initials: HM
authors.lastname: Wang
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Mehrnoush
authors.initials: M
authors.lastname: Malekesmaeili
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Ryan R
authors.initials: RR
authors.lastname: Brinkman
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, BC, Canada; Leukemia/Bone Marrow Transplant Program of British Columbia, British Columbia Cancer Agency, Vancouver, BC, Canada; and.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Forrest
authors.affiliation: Genome Sciences Centre and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Gorski
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Medical Genetics and Department of Medicine, University of British Columbia, Vancouver, BC, Canada;
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000328:Adult; D018952:Antigens, CD34 / Q000378:metabolism; D001343:Autophagy / Q000235:genetics; D000071183:Autophagy-Related Proteins; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis* / Q000473:pathology / Q000628:therapy; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: D018952:Antigens, CD34; D000071183:Autophagy-Related Proteins; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; C507524:ATG4B protein, human; D003546:Cysteine Endopeptidases