Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
Australian Centre for Blood Diseases, Monash University, Commercial Road, Melbourne, VIC 3004, Australia.
Cell Stem Cell. 2019 Aug 1;25(2):258-272.e9. doi: 10.1016/j.stem.2019.07.001.
Tumors are composed of phenotypically heterogeneous cancer cells that often resemble various differentiation states of their lineage of origin. Within this hierarchy, it is thought that an immature subpopulation of tumor-propagating cancer stem cells (CSCs) differentiates into non-tumorigenic progeny, providing a rationale for therapeutic strategies that specifically eradicate CSCs or induce their differentiation. The clinical success of these approaches depends on CSC differentiation being unidirectional rather than reversible, yet this question remains unresolved even in prototypically hierarchical malignancies, such as acute myeloid leukemia (AML). Here, we show in murine and human models of AML that, upon perturbation of endogenous expression of the lineage-determining transcription factor PU.1 or withdrawal of established differentiation therapies, some mature leukemia cells can de-differentiate and reacquire clonogenic and leukemogenic properties. Our results reveal plasticity of CSC maturation in AML, highlighting the need to therapeutically eradicate cancer cells across a range of differentiation states.
肿瘤由表型异质性的癌细胞组成，这些癌细胞通常类似于其起源谱系的各种分化状态。在这个层次结构中，人们认为具有增殖能力的肿瘤起始癌干细胞（CSC）的一个不成熟亚群分化为非致瘤性祖细胞，为专门消灭 CSC 或诱导其分化的治疗策略提供了合理依据。这些方法的临床成功取决于 CSC 分化是单向的而不是可逆的，但即使在急性髓系白血病（AML）等典型的分层恶性肿瘤中，这个问题仍然没有得到解决。在这里，我们在 AML 的小鼠和人类模型中表明，在干扰谱系决定转录因子 PU.1 的内源性表达或停止既定的分化治疗后，一些成熟的白血病细胞可以去分化并重新获得集落形成和白血病形成特性。我们的结果揭示了 AML 中 CSC 成熟的可塑性，强调了需要在一系列分化状态下通过治疗性地消灭癌细胞。
