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MUC1-mediated induction of myeloid-derived suppressor cells in patients with acute myeloid leukemia.
Pyzer, Athalia Rachel; Stroopinsky, Dina; Rajabi, Hasan; Washington, Abigail; Tagde, Ashujit; Coll, Maxwell; Fung, Jacqueline; Bryant, Mary Paty; Cole, Leandra; Palmer, Kristen; Somaiya, Poorvi; Karp Leaf, Rebecca; Nahas, Myrna; Apel, Arie; Jain, Salvia; McMasters, Malgorzata; Mendez, Lourdes; Levine, James; Joyce, Robin; Arnason, Jon; Pandolfi, Pier Paolo; Kufe, Donald; Rosenblatt, Jacalyn; Avigan, David.
Afiliação
  • Pyzer AR; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
  • Stroopinsky D; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
  • Rajabi H; Dana Farber Cancer Institute, and.
  • Washington A; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
  • Tagde A; Dana Farber Cancer Institute, and.
  • Coll M; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
  • Fung J; Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA.
  • Bryant MP; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
  • Cole L; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
  • Palmer K; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
  • Somaiya P; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
  • Karp Leaf R; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
  • Nahas M; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
  • Apel A; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
  • Jain S; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
  • McMasters M; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
  • Mendez L; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
  • Levine J; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
  • Joyce R; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
  • Arnason J; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
  • Pandolfi PP; Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA.
  • Kufe D; Dana Farber Cancer Institute, and.
  • Rosenblatt J; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
  • Avigan D; Department of Bone Marrow Transplantation, Beth Israel Deaconess Medical Center.
Blood ; 129(13): 1791-1801, 2017 Mar 30.
Article em En | MEDLINE | ID: mdl-28126925
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Mucina-1 / Proliferação de Células / Células Supressoras Mieloides Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Mucina-1 / Proliferação de Células / Células Supressoras Mieloides Idioma: En Ano de publicação: 2017 Tipo de documento: Article