Martiáñez Canales Tania, de Leeuw David C, Vermue Eline, Ossenkoppele Gert J, Smit Linda
Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Cancers (Basel). 2017 Jun 30;9(7):74. doi: 10.3390/cancers9070074.
For over 40 years the standard treatment for acute myeloid leukemia (AML) patients has been a combination of chemotherapy consisting of cytarabine and an anthracycline such as daunorubicin. This standard treatment results in complete remission (CR) in the majority of AML patients. However, despite these high CR rates, only 30-40% (<60 years) and 10-20% (>60 years) of patients survive five years after diagnosis. The main cause of this treatment failure is insufficient eradication of a subpopulation of chemotherapy resistant leukemic cells with stem cell-like properties, often referred to as "leukemic stem cells" (LSCs). LSCs co-exist in the bone marrow of the AML patient with residual healthy hematopoietic stem cells (HSCs), which are needed to reconstitute the blood after therapy. To prevent relapse, development of additional therapies targeting LSCs, while sparing HSCs, is essential. As LSCs are rare, heterogeneous and dynamic, these cells are extremely difficult to target by single gene therapies. Modulation of miRNAs and consequently the regulation of hundreds of their targets may be the key to successful elimination of resistant LSCs, either by inducing apoptosis or by sensitizing them for chemotherapy. To address the need for specific targeting of LSCs, miRNA expression patterns in highly enriched HSCs, LSCs, and leukemic progenitors, all derived from the same patients' bone marrow, were determined and differentially expressed miRNAs between LSCs and HSCs and between LSCs and leukemic progenitors were identified. Several of these miRNAs are specifically expressed in LSCs and/or HSCs and associated with AML prognosis and treatment outcome. In this review, we will focus on the expression and function of miRNAs expressed in normal and leukemic stem cells that are residing within the AML bone marrow. Moreover, we will review their possible prospective as specific targets for anti-LSC therapy.
40多年来，急性髓系白血病（AML）患者的标准治疗方法一直是使用阿糖胞苷和柔红霉素等蒽环类药物联合化疗。这种标准治疗使大多数AML患者实现完全缓解（CR）。然而，尽管CR率很高，但诊断后存活五年的患者仅占30 - 40%（<60岁）和10 - 20%（>60岁）。这种治疗失败的主要原因是未能充分根除具有干细胞样特性的化疗耐药白血病细胞亚群，通常称为“白血病干细胞”（LSCs）。LSCs与AML患者骨髓中的残留健康造血干细胞（HSCs）共存，而这些HSCs是治疗后重建血液所必需的。为防止复发，开发针对LSCs同时保护HSCs的额外疗法至关重要。由于LSCs罕见、异质性且具有动态性，这些细胞极难通过单一基因疗法靶向。调节miRNA及其数百个靶标的调控可能是成功消除耐药LSCs的关键，无论是通过诱导凋亡还是使它们对化疗敏感。为满足对LSCs特异性靶向的需求，我们测定了来自同一患者骨髓的高度富集的HSCs、LSCs和白血病祖细胞中的miRNA表达模式，并鉴定了LSCs与HSCs以及LSCs与白血病祖细胞之间差异表达的miRNA。其中一些miRNA在LSCs和/或HSCs中特异性表达，并与AML预后和治疗结果相关。在本综述中，我们将重点关注AML骨髓中正常和白血病干细胞中表达的miRNA的表达和功能。此外，我们将综述它们作为抗LSC治疗特异性靶点的可能前景。
