Division of Hematology and Medical Oncology, Oregon Health and Science University Cancer Institute, Portland, Oregon, USA.
J Clin Invest. 2011 Jan;121(1):396-409. doi: 10.1172/JCI35721. Epub 2010 Dec 13.
Imatinib therapy, which targets the oncogene product BCR-ABL, has transformed chronic myeloid leukemia (CML) from a life-threatening disease into a chronic condition. Most patients, however, harbor residual leukemia cells, and disease recurrence usually occurs when imatinib is discontinued. Although various mechanisms to explain leukemia cell persistence have been proposed, the critical question from a therapeutic standpoint--whether disease persistence is BCR-ABL dependent or independent--has not been answered. Here, we report that human CML stem cells do not depend on BCR-ABL activity for survival and are thus not eliminated by imatinib therapy. Imatinib inhibited BCR-ABL activity to the same degree in all stem (CD34+CD38-, CD133+) and progenitor (CD34+CD38+) cells and in quiescent and cycling progenitors from newly diagnosed CML patients. Although short-term in vitro imatinib treatment reduced the expansion of CML stem/progenitors, cytokine support permitted growth and survival in the absence of BCR-ABL activity that was comparable to that of normal stem/progenitor counterparts. Our findings suggest that primitive CML cells are not oncogene addicted and that therapies that biochemically target BCR-ABL will not eliminate CML stem cells.
伊马替尼治疗针对致癌基因产物 BCR-ABL，已将慢性髓细胞白血病（CML）从一种危及生命的疾病转变为慢性疾病。然而，大多数患者仍存在残留白血病细胞，当停止使用伊马替尼时，疾病通常会复发。尽管已经提出了各种解释白血病细胞持续存在的机制，但从治疗角度来看的关键问题——疾病持续是否依赖于 BCR-ABL——尚未得到解答。在这里，我们报告人类 CML 干细胞的存活不依赖于 BCR-ABL 活性，因此不会被伊马替尼治疗消除。伊马替尼以相同的程度抑制所有干细胞（CD34+CD38-，CD133+）和祖细胞（CD34+CD38+）以及来自新诊断 CML 患者的静止和循环祖细胞中的 BCR-ABL 活性。尽管短期体外伊马替尼治疗减少了 CML 干细胞/祖细胞的扩增，但细胞因子支持允许在没有 BCR-ABL 活性的情况下进行生长和存活，与正常干细胞/祖细胞相当。我们的发现表明原始 CML 细胞不是致癌基因成瘾的，并且生物化学靶向 BCR-ABL 的治疗不会消除 CML 干细胞。
