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.