title: Leukemia-initiating cells in human T-lymphoblastic leukemia exhibit glucocorticoid resistance.
abstract: T-cell acute lymphoblastic leukemia (T-ALL) is associated with a significant risk of disease relapse, but the biological basis for relapse is poorly understood. Here, we identify leukemiainitiating cells (L-ICs) on the basis of functional assays and prospective isolation and report a role for L-ICs in T-ALL disease and relapse. Long-term proliferation in response to NOTCH1 activating signals in OP9-DL1 coculture system or capacity to initiate leukemia in xenografts by the CD7(+)CD1a(-) subset of primary T-ALL samples was superior to other subsets, refining the identity of T-ALL L-ICs. T-ALL engraftment was improved in nonobese diabetic/severe combined immunodeficiency (NOD/scid)IL2Rγ(null) (NSG) mice compared with NOD/scid with anti-CD122 treatment (NS122), but both showed changes in leukemia immunophenotype. Clonal analysis of xenografts using the TCRG locus revealed the presence of subclones of T-ALL L-ICs, some of which possess a selective growth advantage and correlated with the capacity of CD7(+)CD1a(+) xenograft cells to engraft secondary NSG mice. Treatment of high-risk T-ALL xenografts eliminated CD1a(+) T-ALL cells, but CD1a(-) cells were resistant and their number was increased. Our results establish that primary CD1a(-) T-ALL cells are functionally distinct from CD1a(+) cells and that the CD7(+)CD1a(-) subset is enriched for L-IC activity that may be involved in mediating disease relapse after therapy.
authors.affiliation: Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Priscilla P L
authors.initials: PP
authors.lastname: Chiu
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
mesh_terms: D000818:Animals; D018949:Antigens, CD1; D019011:Antigens, CD7; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D049109:Cell Proliferation; D002999:Clone Cells / Q000473:pathology; D018920:Coculture Techniques; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation / Q000473:pathology*; D051881:Receptor, Notch1 / Q000378:metabolism; D012008:Recurrence; D014183:Transplantation, Heterologous
chemical_list: D018949:Antigens, CD1; D019011:Antigens, CD7; D018931:Antineoplastic Agents, Hormonal; C419393:CD1a antigen; D005938:Glucocorticoids; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D003907:Dexamethasone