Persistence of leukemia stem cells in chronic myelogenous leukemia patients in prolonged remission with imatinib treatment
A partir d'échantillons sanguins prélevés sur des patients atteints d'une leucémie myéloïde chronique et traités à l'aide d'imatinib pendant quatre ans ou plus, cette étude montre la présence persistante de cellules souches surexprimant BCR-ABL
Imatinib mesylate (IM) treatment markedly reduces the burden of leukemia cells in chronic myelogenous leukemia (CML) patients. However, patients remain at risk for relapse on discontinuing treatment. We have previously shown that residual BCR-ABL+ progenitors can be detected in CML patients within the first two years of IM treatment. However reduced rates of relapse and continued decline of BCR-ABL levels with prolonged IM treatment, together with the ability of selected patients to maintain remission after discontinuing IM treatment, led us to investigate whether prolonged IM exposure resulted in reduction or elimination of BCR-ABL+ stem cells. We evaluated BCR-ABL expression in CD34+CD38+ (38+) committed progenitors and CD34+CD38- (38-) stem/primitive progenitor cells in samples from CML patients on IM treatment for at least 4 years with cytogenetic and molecular response. We observed that high levels of BCR-ABL expression were maintained over time in the 38- stem cell fraction. The absolute frequency of BCR-ABL+ cells as determined by limiting dilution analysis was consistently higher in 38- compared with 38+ cells. Transplantation into NOD/SCID-IL2Rγ-chain knockout mice demonstrated that BCR-ABL+ cells had long-term in vivo repopulating capacity. These results directly demonstrate that BCR-ABL+ stem cells persist in CML patients despite prolonged treatment with IM, and support ongoing efforts to target this population.