title: A novel AHI-1-BCR-ABL-DNM2 complex regulates leukemic properties of primitive CML cells through enhanced cellular endocytosis and ROS-mediated autophagy.
abstract: Tyrosine kinase inhibitor (TKI) therapies induce clinical remission with remarkable effects on chronic myeloid leukemia (CML). However, very few TKIs completely eradicate the leukemic clone and persistence of leukemic stem cells (LSCs) remains challenging, warranting new, distinct targets for improved treatments. We demonstrated that the scaffold protein AHI-1 is highly deregulated in LSCs and interacts with multiple proteins, including Dynamin-2 (DNM2), to mediate TKI-resistance of LSCs. We have now demonstrated that the SH3 domain of AHI-1 and the proline rich domain of DNM2 are mainly responsible for this interaction. DNM2 expression was significantly increased in CML stem/progenitor cells; knockdown of DNM2 greatly impaired their survival and sensitized them to TKI treatments. Importantly, a new AHI-1-BCR-ABL-DNM2 protein complex was uncovered, which regulates leukemic properties of these cells through a unique mechanism of cellular endocytosis and ROS-mediated autophagy. Thus, targeting this complex may facilitate eradication of LSCs for curative therapies.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.|Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: K
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: R
authors.initials: R
authors.lastname: Yen
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Fruhstorfer
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Maetzig
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, BC, Canada.|Leukemia/BMT Program of British Columbia, Vancouver, BC, Canada.
authors.forename: D L
authors.initials: DL
authors.lastname: Forrest
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.|Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: R K
authors.initials: RK
authors.lastname: Humphries
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.|Department of Medicine, University of British Columbia, Vancouver, BC, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: X
authors.initials: X
authors.lastname: Jiang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D033942:Adaptor Proteins, Vesicular Transport; D001343:Autophagy; D045744:Cell Line, Tumor; D034285:Dynamin II; D034281:Dynamins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism / Q000502:physiology*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: C487178:AHI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D016044:Fusion Proteins, bcr-abl; C000593490:DNM2 protein, human; D034285:Dynamin II; D034281:Dynamins