白血病细胞的去分化和分化现象及相关调控机制研究

Leukemia stem cells (LSCs) can either self-renew or differentiate in vivo.The spontaneous or induced differentiation of LSCs potentially depletes their leukemogenic potential. However, very little is known about the cellular path that LSCs'differentiation follows and the relevant molecular mechanisms, impeding the development and clinical application of the tumor differentiation-induction therapy. Acute promyelocytic leukemia (APL) represents an intriguing model for understanding the all-trans retinoid acid (ATRA) induced differentiation of leukemia cells. Recently in a preliminary study we have characterized the developmental hierarchy of a mouse APL model. We have found that the promyelocyte-like APL LSCs need to go through the partailly differentiated (PD) stages to reach the full maturation stage and get rid of leukemogenic potential. Interestingly, although the mouse promyelocyte-like APL LSCs immediately embark on the myeloid differentiation in response to ATRA, the majority of the progenies, rather than directly maturing into the neutrophils as previously assumed, will accumulated at a PD-like stage. Moreover, this RA-induced PD APL subset, or the spontaneously generated PD subset alike, can not only differentiate further into the terminal myeloid cells, but also retain a reduced but otherwise measurable potential to reinitiate the original type of APL, clearly via a de-differentiation process. In this proposed study, we will focus on investigating the key molecular mechanisms that goven the fate choice of PD APL cells to either de-differentiation or further maturation. We believe that the conduction of this proposed study will not only set a nice in vivo model for cracking down the secrecy of the de-differentiation phenomenon that exists in numerous types of maligancies, but also provides the experimental basis for further improving the clinical cure rate of APL patients(currently about 90%).

白血病干细胞在体内不但可进行自我更新样扩增,也可发生自发分化而失去致瘤力。全反式维甲酸（ATRA）诱导的急性早幼粒细胞白血病（APL）的髓系分化是肿瘤细胞分化诱导疗法的一重要模型和成功范例，但白血病细胞如何分化并不清楚。我们新近发现类早幼粒样APL白血病干细胞需经过一个部分分化的类中幼粒细胞阶段才可到达终末成熟阶段和失去致瘤力，而部分分化的APL细胞在体内具有二种发育潜能：1)去分化重新变为APL干细胞或2)继续分化成熟。初步结果提示：部分分化的APL细胞的去分化能力可能是ATRA诱导分化疗法后疾病复发的主要原因之一。在本项目中，我们提出对调控APL细胞去分化或分化方向的内在分子机制进行进一步的研究。这项研究的实施不但为进一步提高APL治愈率（目前5年生存率 约90%）提供新的实验基础，也为理解在多种类型肿瘤中存在的"去分化"这一特殊生物学现象提供一便利的研究模型。

诱导分化疗法被认为是一种合理的清除白血病起始细胞（LIC）的策略或方法。然而，在临床上极具有代表性的、全反式维甲酸（ATRA）靶向致癌融合蛋白PML／RARa诱导急性早幼粒白血病（APL）细胞粒系分化的模型中，LIC并不能被完全清除，相关的细胞学和分子机制尚不清楚。与此相关，约15%的APL病例不能被基于ATRA或ATO的联合疗法所治愈，提示ATRA或ATO（三氧化二砷）有可能不能完全逆转PML／RARa所致的致癌性改变。在这项研究中，我们发现处于白血病恶性阶层结构顶端的所谓aLIC通过一个中级部分分化iLIC才能分化为成熟的、所谓MLC。有趣的是，ATRA虽可去除aLIC，但几乎不能去除iLIC。并且iLIC可通过去分化重新生成aLIC。另外，我们还发现，虽然APL细胞在体内接受ATRA或ATO治疗以后出现明显的粒系分化，大部分被PML／RARa异常调节的基因并不能恢复。其中，我们发现IRF8是受PML／RARa抑制但对ATRA和ATO反应不良的重要抑癌基因。体内实验提示IRF8 过表达可抑制APL的白血病干性，与ATRA合用则可清除APL细胞的白血病重建能力。这些结果丰富了我们对LIC异质性的认识，提示IRF8 诱导是一种可开发的治疗APL（特别是ATRA／ATO抵抗的病例）的新策略。

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