title: Persistence of leukemia stem cells in chronic myelogenous leukemia patients in prolonged remission with imatinib treatment.
abstract: Imatinib mesylate 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 2 years of imatinib treatment. However, reduced rates of relapse and continued decline of BCR-ABL levels with prolonged treatment, together with the ability of selected patients to maintain remission after discontinuing treatment, led us to investigate whether prolonged imatinib 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 imatinib treatment for at least 4 years with cytogenetic and molecular response. 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 imatinib, and support ongoing efforts to target this population.
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Chu
authors.forename: Tinisha
authors.initials: T
authors.lastname: McDonald
authors.forename: Allen
authors.initials: A
authors.lastname: Lin
authors.forename: Sujata
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Qin
authors.initials: Q
authors.lastname: Huang
authors.forename: David S
authors.initials: DS
authors.lastname: Snyder
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D001549:Benzamides; D001853:Bone Marrow / Q000473:pathology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D018365:Neoplasm, Residual / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D012074:Remission Induction; D013375:Substance Withdrawal Syndrome / Q000473:pathology; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl