Targeting of CD44 eradicates human acute myeloid leukemic stem cells.
The long-term survival of patients with acute myeloid leukemia (AML) is dismally poor. A permanent cure of AML requires elimination of leukemic stem cells (LSCs), the only cell type capable of initiating and maintaining the leukemic clonal hierarchy. We report a therapeutic approach using an activating monoclonal antibody directed to the adhesion molecule CD44. In vivo administration of this antibody to nonobese diabetic-severe combined immune-deficient mice transplanted with human AML markedly reduced leukemic repopulation. Absence of leukemia in serially transplanted mice demonstrated that AML LSCs are directly targeted. Mechanisms underlying this eradication included interference with transport to stem cell-supportive microenvironmental niches and alteration of AML-LSC fate, identifying CD44 as a key regulator of AML LSCs. The finding that AML LSCs require interaction with a niche to maintain their stem cell properties provides a therapeutic strategy to eliminate quiescent AML LSCs and may be applicable to other types of cancer stem cells.
Jin
Liqing
L
Division of Cell and Molecular Biology, University Health Network Suite 8-355, Toronto Medical Discovery Tower, 101 College Street, Toronto, M5G 1L7, Canada.
Hope
Kristin J
KJ
Zhai
Qiongli
Q
Smadja-Joffe
Florence
F
Dick
John E
JE
D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D018952:Antigens, CD34 / Q000096:biosynthesis; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis*; D007167:Immunotherapy / Q000379:methods*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013234:Stem Cells / Q000166:cytology*
D000911:Antibodies, Monoclonal; D018952:Antigens, CD34; D018960:Hyaluronan Receptors; D051997:ADP-ribosyl Cyclase 1