Adnan Awad Shady, Kankainen Matti, Ojala Teija, Koskenvesa Perttu, Eldfors Samuli, Ghimire Bishwa, Kumar Ashwini, Kytölä Soili, Kamel Mahmoud M, Heckman Caroline A, Porkka Kimmo, Mustjoki Satu
Hematology Research Unit Helsinki, Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland.
Blood Adv. 2020 Feb 11;4(3):546-559. doi: 10.1182/bloodadvances.2019000943.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm accounting for ∼15% of all leukemia. Progress of the disease from an indolent chronic phase to the more aggressive accelerated phase or blast phase (BP) occurs in a minority of cases and is associated with an accumulation of somatic mutations. We performed genetic profiling of 85 samples and transcriptome profiling of 12 samples from 59 CML patients. We identified recurrent somatic mutations in ABL1 (37%), ASXL1 (26%), RUNX1 (16%), and BCOR (16%) in the BP and observed that mutation signatures in the BP resembled those of acute myeloid leukemia (AML). We found that mutation load differed between the indolent and aggressive phases and that nonoptimal responders had more nonsilent mutations than did optimal responders at the time of diagnosis, as well as in follow-up. Using RNA sequencing, we identified other than BCR-ABL1 cancer-associated hybrid genes in 6 of the 7 BP samples. Uncovered expression alterations were in turn associated with mechanisms and pathways that could be targeted in CML management and by which somatic alterations may emerge in CML. Last, we showed the value of genetic data in CML management in a personalized medicine setting.
慢性髓性白血病（CML）是一种骨髓增殖性肿瘤，约占所有白血病的15%。少数情况下，该疾病会从惰性慢性期进展为更具侵袭性的加速期或急变期（BP），这与体细胞突变的积累有关。我们对59例CML患者的85个样本进行了基因分型，并对12个样本进行了转录组分析。我们在BP期发现ABL1（37%）、ASXL1（26%）、RUNX1（16%）和BCOR（16%）存在复发性体细胞突变，并观察到BP期的突变特征与急性髓性白血病（AML）相似。我们发现惰性期和侵袭期的突变负荷不同，在诊断时以及随访中，非最佳反应者比最佳反应者有更多的非同义突变。通过RNA测序，我们在7个BP样本中的6个样本中发现了除BCR-ABL1之外的癌症相关融合基因。发现的表达改变反过来与CML治疗中可能靶向的机制和途径相关，并且体细胞改变可能通过这些机制和途径在CML中出现。最后，我们展示了基因数据在个性化医疗环境下CML治疗中的价值。
