title: MUC1-mediated induction of myeloid-derived suppressor cells in patients with acute myeloid leukemia.
abstract: Myeloid-derived suppressor cells (MDSCs) play a critical role in promoting immune tolerance and disease growth. The mechanism by which tumor cells evoke the expansion of MDSCs in acute myeloid leukemia (AML) has not been well described. We have demonstrated that patients with AML exhibit increased presence of MDSCs in their peripheral blood, in comparison with normal controls. Cytogenetic studies demonstrated that MDSCs in patients with AML may be derived from leukemic or apparently normal progenitors. Engraftment of C57BL/6 mice with TIB-49 AML led to an expansion of CD11b+Gr1+MDSCs in bone marrow and spleen. Coculture of the AML cell lines MOLM-4, THP-1 or primary AML cells with donor peripheral blood mononuclear cells elicited a cell contact-dependent expansion of MDSCs. MDSCs were suppressive of autologous T-cell responses as evidenced by reduced T-cell proliferation and a switch from a Th1 to a Th2 phenotype. We hypothesized that the expansion of MDSCs in AML is accomplished by tumor-derived extracellular vesicles (EVs). Using tracking studies, we demonstrated that AML EVs are taken-up myeloid progenitor cells, resulting in the selective proliferation of MDSCs in comparison with functionally competent antigen-presenting cells. The MUC1 oncoprotein was subsequently identified as the critical driver of EV-mediated MDSC expansion. MUC1 induces increased expression of c-myc in EVs that induces proliferation in the target MDSC population via downstream effects on cell cycle proteins. Moreover, we demonstrate that the microRNA miR34a acts as the regulatory mechanism by which MUC1 drives c-myc expression in AML cells and EVs.
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: Athalia Rachel
authors.identifier: http://orcid.org/0000-0002-0506-1887
authors.initials: AR
authors.lastname: Pyzer
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: Dina
authors.initials: D
authors.lastname: Stroopinsky
authors.affiliation: Dana Farber Cancer Institute, and.
authors.forename: Hasan
authors.initials: H
authors.lastname: Rajabi
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: Abigail
authors.initials: A
authors.lastname: Washington
authors.affiliation: Dana Farber Cancer Institute, and.
authors.forename: Ashujit
authors.initials: A
authors.lastname: Tagde
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: Maxwell
authors.initials: M
authors.lastname: Coll
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Fung
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: Mary Paty
authors.initials: MP
authors.lastname: Bryant
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: Leandra
authors.initials: L
authors.lastname: Cole
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: Kristen
authors.initials: K
authors.lastname: Palmer
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: Poorvi
authors.initials: P
authors.lastname: Somaiya
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Karp Leaf
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: Myrna
authors.initials: M
authors.lastname: Nahas
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: Arie
authors.initials: A
authors.lastname: Apel
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: Salvia
authors.initials: S
authors.lastname: Jain
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: McMasters
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Mendez
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: James
authors.initials: J
authors.lastname: Levine
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: Robin
authors.initials: R
authors.lastname: Joyce
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: Jon
authors.initials: J
authors.lastname: Arnason
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.affiliation: Dana Farber Cancer Institute, and.
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: Jacalyn
authors.initials: J
authors.lastname: Rosenblatt
authors.affiliation: Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
authors.forename: David
authors.initials: D
authors.lastname: Avigan
mesh_terms: D000818:Animals; D002450:Cell Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D000067128:Extracellular Vesicles / Q000473:pathology; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D007963:Leukocytes, Mononuclear; D051379:Mice; D035683:MicroRNAs / Q000502:physiology; D018396:Mucin-1 / Q000502:physiology*; D000072737:Myeloid-Derived Suppressor Cells / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis
chemical_list: C522425:MIRN34 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D018396:Mucin-1; D016271:Proto-Oncogene Proteins c-myc