Zheng Xiaomin, Seshire Anita, Rüster Brigitte, Bug Gesine, Beissert Tim, Puccetti Elena, Hoelzer Dieter, Henschler Reinhard, Ruthardt Martin
Laboratory of Tumor Stem Cell Biology, Department of Hematology, J.W. Goethe University, Frankfurt, Germany.
Haematologica. 2007 Mar;92(3):323-31. doi: 10.3324/haematol.10541.
Stem cells play an important role in the pathogenesis and maintenance of most malignant tumors. Acute myeloid leukemia (AML) is a stem cell disease. The inefficient targeting of the leukemic stem cells (LSC) is considered responsible for relapse after the induction of complete hematologic remission (CR) in AML. Acute promyelocytic leukemia (APL) is a subtype of AML characterized by the t(15;17) translocation and expression of the PML/RARalpha fusion protein. Treatment of APL with all-trans retinoic acid (ATRA) induces CR, but not molecular remission (CMR), because the fusion transcript remains detectable, followed by relapse within a few months. Arsenic induces high rates of CR and CMR followed by a long relapse-free survival (RFS). Here we compared the effects of ATRA and arsenic on PML/RARalpha-positive stem cell compartments.
As models for the PML/RARalpha-positive LSC we used: (i) Sca1+/lin- murine HSC retrovirally transduced with PML/RARalpha; (ii) LSC from mice with PML/RARalpha-positive leukemia; (iii) the side population of the APL cell line NB4.
In contrast to ATRA, arsenic abolishes the aberrant stem cell capacity of PML/RARalpha-positive stem cells. Arsenic had no apparent influence on the proliferation of PML/RARalpha-positive stem cells, whereas ATRA greatly increased the proliferation of these cells. Furthermore ATRA induces proliferation of APL-derived stem cells, whereas arsenic inhibits their growth.
Taken together our data suggest a relationship between the capacity of a compound to target the leukemia-initiating cell and its ability to induce long relapse-free survival. These data strongly support the importance of efficient LSC-targeting for the outcome of patients with leukemia.
干细胞在大多数恶性肿瘤的发病机制及维持过程中发挥重要作用。急性髓系白血病（AML）是一种干细胞疾病。白血病干细胞（LSC）靶向治疗效率低下被认为是AML诱导完全血液学缓解（CR）后复发的原因。急性早幼粒细胞白血病（APL）是AML的一种亚型，其特征为t(15;17)易位及PML/RARα融合蛋白的表达。用全反式维甲酸（ATRA）治疗APL可诱导CR，但不能诱导分子学缓解（CMR），因为融合转录本仍可检测到，随后在数月内复发。砷可诱导高比例的CR和CMR，并伴有较长的无复发生存期（RFS）。在此，我们比较了ATRA和砷对PML/RARα阳性干细胞区室的影响。
作为PML/RARα阳性LSC的模型，我们使用了：（i）用PML/RARα逆转录病毒转导的Sca1+/lin-小鼠造血干细胞（HSC）；（ii）来自PML/RARα阳性白血病小鼠的LSC；（iii）APL细胞系NB4的侧群细胞。
与ATRA相反，砷消除了PML/RARα阳性干细胞异常的干细胞能力。砷对PML/RARα阳性干细胞的增殖无明显影响，而ATRA则显著增加了这些细胞的增殖。此外，ATRA诱导APL来源干细胞的增殖，而砷抑制其生长。
综合我们的数据表明，一种化合物靶向白血病起始细胞的能力与其诱导长无复发生存期的能力之间存在关联。这些数据有力地支持了有效靶向LSC对白血病患者预后的重要性。
