Persistent Malignant Stem Cells in del(5q) Myelodysplasia in Remission
Persistent Malignant Stem Cells in del(5q) Myelodysplasia in Remission
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DOI：
10.1056/nejmoa0912228
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发表时间：
2010-09-09
影响因子：
158.5
通讯作者：
Jacobsen, Sten Eirik W.
中科院分区：
文献类型：
--
作者：
Tehranchi, Ramin;Woll, Petter S.;Jacobsen, Sten Eirik W.
背景
恶性干细胞在体内的临床意义仍不明确。
方法
患有5q缺失（del[5q]）骨髓增生异常综合征（涉及5号染色体长臂的间质缺失）的患者对来那度胺治疗有完全的临床和细胞遗传学缓解，但他们经常复发。为了确定罕见但独特的恶性干细胞的持续存在是否是这种复发的原因，我们检查了从7名患有del(5q)骨髓增生异常综合征的患者获取的骨髓标本，这些患者在接受来那度胺治疗时不再依赖输血并进入细胞遗传学缓解。
结果
几乎所有的CD34⁺、CD38⁺祖细胞以及CD34和CD90阳性、CD38不可检测或低表达（CD38⁻/低）的干细胞在治疗前都有5q缺失。尽管来那度胺在完全缓解的患者中有效地减少了这些祖细胞，但更多的少量的、静止的、CD34⁺、CD38⁻/低、CD90⁺的del(5q)干细胞以及功能上确定的del(5q)干细胞对来那度胺明显耐药。随着时间的推移，大多数部分缓解和完全缓解的患者出现来那度胺耐药，del(5q)克隆复发或扩增以及临床和细胞遗传学进展。
结论
在这些患有del(5q)骨髓增生异常综合征的患者中，我们鉴定出了罕见的且表型独特的del(5q)骨髓增生异常综合征干细胞，这些干细胞在完全临床和细胞遗传学缓解时也对治疗靶向具有选择性耐药。（由欧洲癌症干细胞联盟等资助）
BACKGROUNDThe in vivo clinical significance of malignant stem cells remains unclear.METHODSPatients who have the 5q deletion (del[5q]) myelodysplastic syndrome (interstitial deletions involving the long arm of chromosome 5) have complete clinical and cytogenetic remissions in response to lenalidomide treatment, but they often have relapse. To determine whether the persistence of rare but distinct malignant stem cells accounts for such relapses, we examined bone marrow specimens obtained from seven patients with the del(5q) myelodysplastic syndrome who became transfusion-independent while receiving lenalidomide treatment and entered cytogenetic remission.RESULTSVirtually all CD34+, CD38+ progenitor cells and stem cells that were positive for CD34 and CD90, with undetectable or low CD38 (CD38-/low), had the 5q deletion before treatment. Although lenalidomide efficiently reduced these progenitors in patients in complete remission, a larger fraction of the minor, quiescent, CD34+, CD38-/low, CD90+ del(5q) stem cells as well as functionally defined del(5q) stem cells remained distinctly resistant to lenalidomide. Over time, lenalidomide resistance developed in most of the patients in partial and complete remission, with recurrence or expansion of the del(5q) clone and clinical and cytogenetic progression.CONCLUSIONSIn these patients with the del(5q) myelodysplastic syndrome, we identified rare and phenotypically distinct del(5q) myelodysplastic syndrome stem cells that were also selectively resistant to therapeutic targeting at the time of complete clinical and cytogenetic remission. (Funded by the EuroCancerStemCell Consortium and others.)