Cancer Res：白血病干细胞的致命弱点

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2014年8月7日 讯 /生物谷BIOON/ --尽管疗法已经得到了极大改善，但是两个成年急性髓性白血病（AML）患者中也仅有一人会生存下去，对于65岁以上的老年人而言，急性髓性白血病平均存活期不到一年；而研究者推测发病原因可能是白血病干细胞，在患者机体中白血病干细胞并不能完全被清除，这些白血病干细胞就是引发患者病情复发最终致死的原因。# _9 u% {$ m! S: j, C
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近日，刊登在国际杂志Cancer Research上的一篇研究论文中，来自歌德大学(Goethe-Universitat Frankfurt am Main)的研究人员通过研究发现了急性髓性白血病干细胞的弱点，他们发现了一种名为5-脂氧合酶(5-LO)的酶类在急性髓性白血病干细胞的生存过程中扮演着重要角色。
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9 z- P! b; V. C% j$ A此前研究人员已经发现了5-LO在炎性疾病比如哮喘症发病中的角色，研究者Jessica Roos教授表示，这项研究中我们发现，急性髓性白血病亚群中的白血病干细胞或许可以被5-LO抑制剂有效地选择性攻击，而且这种现象均可以在细胞培养基模型和白血病小鼠模型中观察到。3 T% z! f2 }0 S

# |# t6 C3 p4 `4 D# j, W7 @. [研究者表示，这项研究为开发新型的5-脂氧合酶抑制剂来抑制白血病的存货，从而为抑制并治疗急性髓性白血病提供了新的研究依据和线索。后期研究中研究人员还将通过深入研究来揭示5-脂氧合酶抑制剂在抑制白血病干细胞功能中的作用和机制。（/ T  F: h1 L1 T. i8 T

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3 ]" q" g; ]" f* K8 cdoi:10.1158/0008-5472.CAN-13-3012
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5-lipoxygenase is a candidate target for therapeutic management of stem cell-like cells in acute myeloid leukemia
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2 R% @/ q1 W5 uJessica Roos1, Claudia Oancea1, Maria Heinssmann1, Dilawar Khan1, Hannelore Held1, Astrid S. Kahnt2, Ricardo Capelo2, Estel la Buscato2, Ewgenij Proschak2, Elena Puccetti3, Dieter Steinhilber2, Ingrid Fleming4, Thorsten J. Maier5, and Martin Ruthardt1,*; ]' S2 V" z2 g7 h/ |, I" F
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Non-steroidal anti-inflammatory drugs such as sulindac inhibit Wnt-signaling, which is critical to maintain cancer stem-cell like cells (CSC), but they also suppress the activity of 5-lipoxygenase (5-LO) at clinically feasible concentrations. Recently, 5-LO was shown to be critical to maintain CSC in a model of chronic myeloid leukemia. For these reasons, we hypothesized that 5-LO may offer a therapeutic target to improve the management of acute myeloid leukemia (AML), an aggressive disease driven by CSC. Pharmacological and genetic approaches were used to evaluate the effects of 5-LO blockade in a PML/RARα -positive model of AML. As CSC models we used Sca-1+/lin- murine hematopoietic stem and progenitor cells (HSPC), which were retrovirally transduced with PML/RARα. We found that pharmacological inhibition of 5-LO interfered strongly with the aberrant stem cell capacity of PML/RARα-expressing HSPC. Through small molecule inhibitor studies and genetic disruption of 5-LO, we also found that Wnt and CSC inhibition is mediated by the enzymatically inactive form of 5-LO which hinders nuclear translocation of ß-catenin. Overall, our findings revealed that 5-LO inhibitors also inhibit Wnt signaling, not due to the interruption of 5-LO-mediated lipid signaling but rather to the generation of a catalytically inactive form of 5-LO which assumes a new function. Given the evidence that CSC mediate AML relapse after remission, eradication of CSC in this setting by 5-LO inhibition may offer a new clinical approach for immediate evaluation in AML patients. 3 d5 G% W; E3 h6 d1 \, U6 X