title: MUC1-C oncoprotein suppresses reactive oxygen species-induced terminal differentiation of acute myelogenous leukemia cells.
abstract: Acute myeloid leukemia (AML) cells are characterized by unlimited self-renewal and an impaired capacity to undergo terminal differentiation. The MUC1 oncoprotein is aberrantly expressed in AML cells; however, there has been no evidence for involvement of MUC1 in myeloid leukemogenesis. Cell-penetrating peptide inhibitors of the MUC1-C subunit block its oligomerization and thereby oncogenic function. The present results demonstrate that treatment of human MOLM-14 and MV4-11 AML cells with these inhibitors is associated with arrest of growth, induction of late apoptosis/necrosis, and loss of self-renewal capacity. Similar results were obtained with primary blasts from patients with AML. Inhibition of MUC1-C was associated with increases in reactive oxygen species (ROS) and depletion of glutathione. Increases in ROS have been linked to induction of hematopoietic cell differentiation along the myeloid lineage. In this regard, inhibition of MUC1-C was associated with induction of a terminally differentiated myeloid phenotype in AML cell lines and primary blasts by an ROS-dependent mechanism. These findings indicate that MUC1-C function is of importance to AML cell self-renewal and that inhibition of MUC1-C represents a potential therapeutic approach to induce terminal differentiation of AML cells.
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yin
authors.forename: Zekui
authors.initials: Z
authors.lastname: Wu
authors.forename: David
authors.initials: D
authors.lastname: Avigan
authors.forename: Jacalyn
authors.initials: J
authors.lastname: Rosenblatt
authors.forename: Richard
authors.initials: R
authors.lastname: Stone
authors.forename: Surender
authors.initials: S
authors.lastname: Kharbanda
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018396:Mucin-1 / Q000737:chemistry / Q000378:metabolism*; D009336:Necrosis; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010641:Phenotype; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: C060192:MUC1 protein, human; D018396:Mucin-1; D009842:Oligopeptides; D017382:Reactive Oxygen Species; D000111:Acetylcysteine