Dipeptidylpeptidase IV (CD26) defines leukemic stem cells (LSC) in chronic myeloid leukemia.
Chronic myeloid leukemia (CML) is a stem cell (SC) neoplasm characterized by the BCR/ABL1 oncogene. Although mechanisms of BCR/ABL1-induced transformation are well-defined, little is known about effector-molecules contributing to malignant expansion and the extramedullary spread of leukemic SC (LSC) in CML. We have identified the cytokine-targeting surface enzyme dipeptidylpeptidase-IV (DPPIV/CD26) as a novel, specific and pathogenetically relevant biomarker of CD34(+)/CD38(─) CML LSC. In functional assays, CD26 was identified as target enzyme disrupting the SDF-1-CXCR4-axis by cleaving SDF-1, a chemotaxin recruiting CXCR4(+) SC. CD26 was not detected on normal SC or LSC in other hematopoietic malignancies. Correspondingly, CD26(+) LSC decreased to low or undetectable levels during successful treatment with imatinib. CD26(+) CML LSC engrafted NOD-SCID-IL-2Rγ(-/-) (NSG) mice with BCR/ABL1(+) cells, whereas CD26(─) SC from the same patients produced multilineage BCR/ABL1(-) engraftment. Finally, targeting of CD26 by gliptins suppressed the expansion of BCR/ABL1(+) cells. Together, CD26 is a new biomarker and target of CML LSC. CD26 expression may explain the abnormal extramedullary spread of CML LSC, and inhibition of CD26 may revert abnormal LSC function and support curative treatment approaches in this malignancy.
Ludwig Boltzmann Cluster Oncology, and.
Harald
H
Herrmann
Department of Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria;
Irina
I
Sadovnik
Ludwig Boltzmann Cluster Oncology, and Department of Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria;
Sabine
S
Cerny-Reiterer
Institute of Laboratory Animal Science and.
Thomas
T
Rülicke
Department of Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria;
Gabriele
G
Stefanzl
Department of Companion Animals and Horses, Clinic for Internal Medicine and Infectious Diseases, University of Veterinary Medicine Vienna, Vienna, Austria;
Michael
M
Willmann
Department of Laboratory Medicine, and.
Gregor
G
Hoermann
Department of Laboratory Medicine, and.
Martin
M
Bilban
Department of Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria;
Katharina
K
Blatt
Department of Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria;
Susanne
S
Herndlhofer
Department of Laboratory Medicine, and.
Matthias
M
Mayerhofer
Institute of Gynecology & Obstetrics, Medical University of Vienna, Vienna, Austria; and.
Berthold
B
Streubel
Ludwig Boltzmann Cluster Oncology, and Department of Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria;
Wolfgang R
WR
Sperr
College of Medical, Veterinary & Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
Tessa L
TL
Holyoake
Department of Laboratory Medicine, and.
Christine
C
Mannhalter
Ludwig Boltzmann Cluster Oncology, and Department of Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria;
Peter
P
Valent
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides / Q000627:therapeutic use; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000068877:Imatinib Mesylate; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008297:Male; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010879:Piperazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D055815:Young Adult
D000970:Antineoplastic Agents; D001549:Benzamides; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D018819:Dipeptidyl Peptidase 4