title: The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells.
abstract: In CD34(+) acute myeloid leukemia (AML), the malignant stem cells reside in the CD38(-) compartment. We have shown before that the frequency of such CD34(+)CD38(-) cells at diagnosis correlates with minimal residual disease (MRD) frequency after chemotherapy and with survival. Specific targeting of CD34(+)CD38(-) cells might thus offer therapeutic options. Previously, we found that C-type lectin-like molecule-1 (CLL-1) has high expression on the whole blast compartment in the majority of AML cases. We now show that CLL-1 expression is also present on the CD34(+)CD38(-) stem- cell compartment in AML (77/89 patients). The CD34(+)CLL-1(+) population, containing the CD34(+)CD38(-)CLL-1(+) cells, does engraft in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with outgrowth to CLL-1(+) blasts. CLL-1 expression was not different between diagnosis and relapse (n = 9). In remission, both CLL-1(-) normal and CLL-1(+) malignant CD34(+)CD38(-) cells were present. A high CLL-1(+) fraction was associated with quick relapse. CLL-1 expression is completely absent both on CD34(+)CD38(-) cells in normal (n = 11) and in regenerating bone marrow controls (n = 6). This AML stem-cell specificity of the anti-CLL-1 antibody under all conditions of disease and the leukemia-initiating properties of CD34(+)CLL-1(+) cells indicate that anti-CLL-1 antibody enables both AML-specific stem-cell detection and possibly antigen-targeting in future.
authors.affiliation: Department of Hematology, VU [Vrije Universiteit] University Medical Center, Amsterdam, The Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: van Rhenen
authors.forename: Guus A M S
authors.initials: GA
authors.lastname: van Dongen
authors.forename: Angèle
authors.initials: A
authors.lastname: Kelder
authors.forename: Elwin J
authors.initials: EJ
authors.lastname: Rombouts
authors.forename: Nicole
authors.initials: N
authors.lastname: Feller
authors.forename: Bijan
authors.initials: B
authors.lastname: Moshaver
authors.forename: Marijke
authors.initials: M
authors.lastname: Stigter-van Walsum
authors.forename: Sonja
authors.initials: S
authors.lastname: Zweegman
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: Gerrit
authors.initials: G
authors.lastname: Jan Schuurhuis
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000378:metabolism*
chemical_list: D018952:Antigens, CD34; C485220:CLEC12A protein, human; C529398:CLEC12A protein, mouse; D037181:Lectins, C-Type; D011975:Receptors, Mitogen; D051997:ADP-ribosyl Cyclase 1