Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy
Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.
Haematologica. 2019 Sep;104(9):1789-1797. doi: 10.3324/haematol.2017.179937. Epub 2019 Feb 28.
Despite the advent of tyrosine kinase inhibitors, a proportion of chronic myeloid leukemia patients in chronic phase fail to respond to imatinib or to second-generation inhibitors and progress to blast crisis. Until now, improvements in the understanding of the molecular mechanisms responsible for chronic myeloid leukemia transformation from chronic phase to the aggressive blast crisis remain limited. Here we present a large parallel sequencing analysis of 10 blast crisis samples and of the corresponding autologous chronic phase controls that reveals, for the first time, recurrent mutations affecting the ubiquitin-conjugating enzyme E2A gene (, formerly ). Additional analyses on a cohort of 24 blast crisis, 41 chronic phase as well as 40 acute myeloid leukemia and 38 atypical chronic myeloid leukemia patients at onset confirmed that mutations are specifically acquired during chronic myeloid leukemia progression, with a frequency of 16.7% in advanced phases. studies show that the mutations here described cause a decrease in UBE2A activity, leading to an impairment of myeloid differentiation in chronic myeloid leukemia cells.
尽管酪氨酸激酶抑制剂已经问世，但仍有一部分处于慢性期的慢性髓性白血病患者对伊马替尼或第二代抑制剂没有反应，并进展为急变期。直到现在，人们对慢性髓性白血病从慢性期向侵袭性急变期转变的分子机制的理解仍有限。在这里，我们对 10 个急变期样本和相应的自体慢性期对照样本进行了大规模平行测序分析，首次揭示了影响泛素连接酶 E2A 基因（以前称为 ）的复发性突变。对 24 例急变期、41 例慢性期以及 40 例急性髓系白血病和 38 例非典型慢性髓系白血病患者的队列分析进一步证实，突变是在慢性髓系白血病进展过程中特异性获得的，在晚期阶段的频率为 16.7%。功能研究表明，这里描述的突变导致 UBE2A 活性降低，从而导致慢性髓系白血病细胞中髓系分化受损。
