title: C-type lectin-like molecule-1: a novel myeloid cell surface marker associated with acute myeloid leukemia.
abstract: Acute myeloid leukemia (AML) has a poor prognosis due to treatment-resistant relapses. A humanized anti-CD33 antibody (Mylotarg) showed a limited response rate in relapsed AML. To discover novel AML antibody targets, we selected a panel of single chain Fv fragments using phage display technology combined with flow cytometry on AML tumor samples. One selected single chain Fv fragment broadly reacted with AML samples and with myeloid cell lineages within peripheral blood. Expression cloning identified the antigen recognized as C-type lectin-like molecule-1 (CLL-1), a previously undescribed transmembrane glycoprotein. CLL-1 expression was analyzed with a human anti-CLL-1 antibody that was generated from the single chain Fv fragment. CLL-1 is restricted to the hematopoietic lineage, in particular to myeloid cells present in peripheral blood and bone marrow. CLL-1 is absent on uncommitted CD34(+)/CD38(-) or CD34(+)/CD33(-) stem cells and present on subsets of CD34(+)/CD38(+) or CD34(+)/CD33(+) progenitor cells. CLL-1 is not expressed in any other tissue. In contrast, analysis of primary AMLs demonstrated CLL-1 expression in 92% (68 of 74) of the samples. As an AML marker, CLL-1 was able to complement CD33, because 67% (8 of 12) of the CD33(-) AMLs expressed CLL-1. CLL-1 showed variable expression (10-60%) in CD34(+) cells in chronic myelogenous leukemia and myelodysplastic syndrome but was absent in 12 of 13 cases of acute lymphoblastic leukemia. The AML reactivity combined with the restricted expression on normal cells identifies CLL-1 as a novel potential target for AML treatment.
authors.affiliation: Crucell Holland B.V., Leiden, The Netherlands. l.bakker@crucell.com
authors.forename: Alexander B H
authors.initials: AB
authors.lastname: Bakker
authors.forename: Sonja
authors.initials: S
authors.lastname: van den Oudenrijn
authors.forename: Arjen Q
authors.initials: AQ
authors.lastname: Bakker
authors.forename: Nicole
authors.initials: N
authors.lastname: Feller
authors.forename: Marja
authors.initials: M
authors.lastname: van Meijer
authors.forename: Judith A
authors.initials: JA
authors.lastname: Bia
authors.forename: Mandy A C
authors.initials: MA
authors.lastname: Jongeneelen
authors.forename: Therese J
authors.initials: TJ
authors.lastname: Visser
authors.forename: Nora
authors.initials: N
authors.lastname: Bijl
authors.forename: Cecilia A W
authors.initials: CA
authors.lastname: Geuijen
authors.forename: Wilfred E
authors.initials: WE
authors.lastname: Marissen
authors.forename: Katarina
authors.initials: K
authors.lastname: Radosevic
authors.forename: Mark
authors.initials: M
authors.lastname: Throsby
authors.forename: Gerrit Jan
authors.initials: GJ
authors.lastname: Schuurhuis
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: John
authors.initials: J
authors.lastname: de Kruif
authors.forename: Jaap
authors.initials: J
authors.lastname: Goudsmit
authors.forename: Ada M
authors.initials: AM
authors.lastname: Kruisbeek
mesh_terms: D000208:Acute Disease; D000595:Amino Acid Sequence; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D037181:Lectins, C-Type / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000378:metabolism*; D008969:Molecular Sequence Data
chemical_list: D014408:Biomarkers, Tumor; D037181:Lectins, C-Type