Leukemic stem cell persistence in chronic myeloid leukemia patients in deep molecular response induced by tyrosine kinase inhibitors and the impact of therapy discontinuation.
Leukemic stem cell persistence in chronic myeloid leukemia patients in deep molecular response induced by tyrosine kinase inhibitors and the impact of therapy discontinuation.
复制标题
DOI：
10.18632/oncotarget.9182
复制
发表时间：
2016-06-07
期刊：
影响因子：
--
通讯作者：
Turhan AG
中科院分区：
文献类型：
--
作者：
Chomel JC;Bonnet ML;Sorel N;Sloma I;Bennaceur-Griscelli A;Rea D;Legros L;Marfaing-Koka A;Bourhis JH;Ame S;Guerci-Bresler A;Rousselot P;Turhan AG
在过去的十年中，酪氨酸激酶抑制剂（TKI）治疗的使用改变了慢性髓性白血病（CML）的自然病程，使总体和无病生存期增加，特别是在分子残留疾病无法检测到的患者中。然而，已经证明表达BCR-ABL1的白血病干细胞（LSCs）在患者中持续存在深层分子反应。研究还表明，在大多数情况下，停止使用伊马替尼会导致分子复发。为了确定这两种现象之间的可能关系，我们通过克隆生成和长期培养起始细胞（LTC-IC）测定，在TKI治疗后3年（平均持续时间7年），21例患者骨髓样本中存在表达bcr - abl1的LSCs。4/21例患者检测到LSCs。13/21患者停止TKI治疗导致5例患者快速分子复发（4例未检测到LSCs， 1例可检测到LSCs）。无论是否检测到LSCs，仍在接受TKI治疗的8例患者均未出现复发。因此，本研究首次证明了TKIs在祖细胞和LSC细胞室中的体内效率。它也证实了白血病干细胞在患者体内的深层分子反应的持久性，当然是复发的起源。最后，它强调了检测残留LSCs的困难，因为它们的稀有性和低BCR-ABL1 mRNA表达。
During the last decade, the use of tyrosine kinase inhibitor (TKI) therapy has modified the natural history of chronic myeloid leukemia (CML) allowing an increase of the overall and disease-free survival, especially in patients in whom molecular residual disease becomes undetectable. However, it has been demonstrated that BCR-ABL1- expressing leukemic stem cells (LSCs) persist in patients in deep molecular response. It has also been shown that the discontinuation of Imatinib leads to a molecular relapse in the majority of cases. To determine a possible relationship between these two phenomena, we have evaluated by clonogenic and long-term culture initiating cell (LTC-IC) assays, the presence of BCR-ABL1-expressing LSCs in marrow samples from 21 patients in deep molecular response for three years after TKI therapy (mean duration seven years). LSCs were detected in 4/21 patients. Discontinuation of TKI therapy in 13/21 patients led to a rapid molecular relapse in five patients (4 without detectable LSCs and one with detectable LSCs). No relapse occurred in the eight patients still on TKI therapy, whether LSCs were detectable or not. Thus, this study demonstrates for the first time the in vivo efficiency of TKIs, both in the progenitor and the LSC compartments. It also confirms the persistence of leukemic stem cells in patients in deep molecular response, certainly at the origin of relapses. Finally, it emphasizes the difficulty of detecting residual LSCs due to their rarity and their low BCR-ABL1 mRNA expression.
登录
查看更多内容
影响因子：
11.4
作者：
Mustjoki, S.;Richter, J.;Hjorth-Hansen, H.
通讯作者：
Hjorth-Hansen, H.
影响因子：
20.3
作者：
Chu, Su;McDonald, Tinisha;Bhatia, Ravi
通讯作者：
Bhatia, Ravi
DOI：
10.1073/pnas.1004408107
发表时间：
2010-09-14
影响因子：
11.1
作者：
Jaras, Marcus;Johnels, Petra;Fioretos, Thoas
通讯作者：
Fioretos, Thoas
影响因子：
2.6
作者：
Caocci, Giovanni;Martino, Bruno;La Nasa, Giorgio
通讯作者：
La Nasa, Giorgio
影响因子：
51.1
作者：
Mahon, Francois-Xavier;Rea, Delphine;Rousselot, Philippe
通讯作者：
Rousselot, Philippe