title: MUC1 is a potential target for the treatment of acute myeloid leukemia stem cells.
abstract: Acute myeloid leukemia (AML) is a malignancy of stem cells with an unlimited capacity for self-renewal. MUC1 is a secreted, oncogenic mucin that is expressed aberrantly in AML blasts, but its potential uses to target AML stem cells have not been explored. Here, we report that MUC1 is highly expressed on AML CD34(+)/lineage(-)/CD38(-) cells as compared with their normal stem cell counterparts. MUC1 expression was not restricted to AML CD34(+) populations as similar results were obtained with leukemic cells from patients with CD34(-) disease. Engraftment of AML stem cell populations that highly express MUC1 (MUC1(high)) led to development of leukemia in NOD-SCID IL2Rgamma(null) (NSG) immunodeficient mice. In contrast, MUC1(low) cell populations established normal hematopoiesis in the NSG model. Functional blockade of the oncogenic MUC1-C subunit with the peptide inhibitor GO-203 depleted established AML in vivo, but did not affect engraftment of normal hematopoietic cells. Our results establish that MUC1 is highly expressed in AML stem cells and they define the MUC1-C subunit as a valid target for their therapeutic eradication.
authors.affiliation: Beth Israel Deaconess Medical Center and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Dina
authors.initials: D
authors.lastname: Stroopinsky
authors.forename: Jacalyn
authors.initials: J
authors.lastname: Rosenblatt
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ito
authors.forename: Heidi
authors.initials: H
authors.lastname: Mills
authors.forename: Li
authors.initials: L
authors.lastname: Yin
authors.forename: Hasan
authors.initials: H
authors.lastname: Rajabi
authors.forename: Baldev
authors.initials: B
authors.lastname: Vasir
authors.forename: Turner
authors.initials: T
authors.lastname: Kufe
authors.forename: Katarina
authors.initials: K
authors.lastname: Luptakova
authors.forename: Jon
authors.initials: J
authors.lastname: Arnason
authors.forename: Caterina
authors.initials: C
authors.lastname: Nardella
authors.forename: James D
authors.initials: JD
authors.lastname: Levine
authors.forename: Robin M
authors.initials: RM
authors.lastname: Joyce
authors.forename: Ilene
authors.initials: I
authors.lastname: Galinsky
authors.forename: Yoram
authors.initials: Y
authors.lastname: Reiter
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
authors.forename: David
authors.initials: D
authors.lastname: Avigan
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018396:Mucin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C582521:(arginine)9-cysteinyl-glutaminyl-cysteinyl-arginyl-arginyl-lysyl-asparagine; D018952:Antigens, CD34; C060192:MUC1 protein, human; D018396:Mucin-1; D010455:Peptides; D012333:RNA, Messenger; D051997:ADP-ribosyl Cyclase 1