Persistence of leukemia stem cells in chronic myelogenous leukemia patients in prolonged remission with imatinib treatment
Persistence of leukemia stem cells in chronic myelogenous leukemia patients in prolonged remission with imatinib treatment
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DOI：
10.1182/blood-2010-12-327437
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发表时间：
2011-11-17
期刊：
影响因子：
20.3
通讯作者：
Bhatia, Ravi
中科院分区：
文献类型：
--
作者：
Chu, Su;McDonald, Tinisha;Bhatia, Ravi
甲磺酸伊马替尼治疗显著减轻慢性粒细胞白血病(CML)患者的白血病细胞负担。然而，患者在停止治疗后仍有复发的风险。我们之前已经证明，在伊马替尼治疗的头两年内，CML患者中可以检测到残留的bcr-abl(+)祖细胞。然而，随着治疗时间的延长，复发率的降低和bcr-abl水平的持续下降，以及选定的患者在停止治疗后保持缓解的能力，我们调查了长期接触伊马替尼是否会导致bcr-abl(+)干细胞的减少或消除。我们用细胞遗传学和分子生物学方法检测了接受伊马替尼治疗至少4年的CML患者样本中CD34(+)、CD38(+)(38(+))定向祖细胞和CD34(+)CD38(-)(38(-))干/原始祖细胞的bcr-abl表达。随着时间的推移，BCR-ABL在38(-)干细胞组分中的高水平表达保持不变。通过极限稀释分析确定的bcr-abl(+)细胞的绝对频率在38(-)细胞中始终高于38(+)细胞。将bcr-abl(+)细胞移植到NOD/SCID-IL2R伽马链基因敲除小鼠体内，表明bcr-abl(+)细胞具有长期体内再繁殖能力。这些结果直接表明，尽管延长了伊马替尼的治疗时间，bcr-abl(+)干细胞仍然存在于CML患者中，并支持针对这一人群的持续努力。(血。2011；118(20)：5565-5572)
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-IL2R gamma-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. (Blood. 2011;118(20):5565-5572)