人们认为几乎所有癌症都是克隆的——是某一个突变的细胞的后代，但从第一个突变到很多不同形式癌症的演化通道在很大程度上仍不知道。John Dick及同事研究了来自“急性髓性白血病”(AML)患者的周围血液和骨髓样本，并在很大比例的患者中识别出了同时有DNMT3Amut 和 NPM1c 突变的白血病细胞。这些患者还有携带DNMT3Amut、但不带NPM1c的白血病前期造血干细胞。这些细胞保持了产生不同细胞类型的能力，因而具有正常造血功能，但相对于野生型造血干细胞在再增殖方面有一个竞争优势，在经过化疗、病情减轻之后能持久存在，因此可能充当一个库的作用，让进一步的突变和对治疗的抵抗力能够积累。这项工作表明DNMT3和其他基因中产生白血病前期造血干细胞的突变是可能的药物作用目标，并且说明白血病前期克隆的识别和处理也许可帮助消除对治疗的抵抗力。
In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3Amut) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3Amut-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3Amut arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance.