title: Endoglin: a novel target for therapeutic intervention in acute leukemias revealed in xenograft mouse models.
abstract: Endoglin (CD105), a receptor of the transforming growth factor-β superfamily, has been reported to identify functional long-term repopulating hematopoietic stem cells, and has been detected in certain subtypes of acute leukemias. Whether this receptor plays a functional role in leukemogenesis remains unknown. We identified endoglin expression on the majority of blasts from patients with acute myeloid leukemia (AML) and acute B-lymphoblastic leukemia (B-ALL). Using a xenograft model, we find that CD105+blasts are endowed with superior leukemogenic activity compared with the CD105-population. We test the effect of targeting this receptor using the monoclonal antibody TRC105, and find that in AML, TRC105 prevented the engraftment of primary AML blasts and inhibited leukemia progression following disease establishment, but in B-ALL, TRC105 alone was ineffective due to the shedding of soluble CD105. However, in both B-ALL and AML, TRC105 synergized with reduced intensity myeloablation to inhibit leukemogenesis, indicating that TRC105 may represent a novel therapeutic option for B-ALL and AML.
authors.affiliation: Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, MN.|Instituto de Ciencias da Saude, Federal University of Bahia, Salvador, Brazil.
authors.forename: Keina M C
authors.initials: KMC
authors.lastname: Dourado
authors.affiliation: Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, MN.
authors.forename: June
authors.initials: J
authors.lastname: Baik
authors.affiliation: Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, MN.
authors.forename: Vanessa K P
authors.initials: VKP
authors.lastname: Oliveira
authors.affiliation: Laboratory for the Diagnosis of Onco-Hematological Disorders, Curitiba, Brazil.
authors.forename: Miriam
authors.initials: M
authors.lastname: Beltrame
authors.affiliation: Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, MN.
authors.forename: Ami
authors.initials: A
authors.lastname: Yamamoto
authors.affiliation: TRACON Pharmaceuticals, Inc, San Diego, CA; and.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Theuer
authors.affiliation: Instituto de Ciencias da Saude, Federal University of Bahia, Salvador, Brazil.
authors.forename: Camila A V
authors.initials: CAV
authors.lastname: Figueiredo
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Verneris
authors.affiliation: Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, MN.
authors.forename: Rita C R
authors.identifier: 0000-0001-9412-1118
authors.initials: RCR
authors.lastname: Perlingeiro
mesh_terms: D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D001752:Blast Crisis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D000071063:Endoglin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D007223:Infant; D019169:Jurkat Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; C064206:ENG protein, human; D000071063:Endoglin; D009363:Neoplasm Proteins; C579557:carotuximab