The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells.
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.
van Rhenen
Anna
A
Department of Hematology, VU [Vrije Universiteit] University Medical Center, Amsterdam, The Netherlands.
van Dongen
Guus A M S
GA
Kelder
Angèle
A
Rombouts
Elwin J
EJ
Feller
Nicole
N
Moshaver
Bijan
B
Stigter-van Walsum
Marijke
M
Zweegman
Sonja
S
Ossenkoppele
Gert J
GJ
Jan Schuurhuis
Gerrit
G
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*
D018952:Antigens, CD34; C485220:CLEC12A protein, human; C529398:CLEC12A protein, mouse; D037181:Lectins, C-Type; D011975:Receptors, Mitogen; D051997:ADP-ribosyl Cyclase 1