Sloma Ivan, Mitjavila-Garcia Maria Teresa, Feraud Olivier, Griscelli Frank, Oudrhiri Noufissa, El Marsafy Sanaa, Gobbo Emilie, Divers Dominique, Proust Alexis, Smadja David M, Desterke Christophe, Carles Annaick, Ma Yusanna, Hirst Martin, Marra Marco A, Eaves Connie J, Bennaceur-Griscelli Annelise, Turhan Ali G
Institut National de la Santé et de la Recherche Médicale (INSERM) U935, Villejuif, France; Service d'Hématologie Biologique, Institut Federatif d'Hematologie Interpôle Paris Sud-IFHIPS (AP-HP) Kremlin Bicêtre, Paris, France; Université Paris-Sud, Faculté de Médecine Kremlin Bicêtre, and INSERM UMS 33, Villejuif, France.
Institut National de la Santé et de la Recherche Médicale (INSERM) U935, Villejuif, France.
Exp Hematol. 2017 Sep;53:48-58. doi: 10.1016/j.exphem.2017.05.007. Epub 2017 Jun 8.
We report here the first use of whole-genome sequencing (WGS) to examine the initial clonal dynamics in an unusual patient with chronic myeloid leukemia (CML), who presented in chronic phase (CP) with doubly marked BCR-ABL1/JAK2-mutant cells and, over a 9-year period, progressed into an accelerated phase (AP) and then terminal blast phase (BP). WGS revealed that the diagnostic cells also contained mutations in ASXL1, SEC23B, MAD1L1, and RREB1 as well as 12,000 additional uncommon DNA variants. WGS of endothelial cells generated from circulating precursors revealed many of these were shared with the CML clone. Surprisingly, WGS of induced pluripotent stem cells (iPSCs) derived from the AP cells revealed only six additional coding somatic mutations, despite retention by the hematopoietic progeny of the parental AP cell levels of BCR-ABL1 expression and sensitivity to imatinib and pimozide. Limited analysis of BP cells revealed independent subclonal progression to homozygosity of the MAD1L1 and RREB1 variants. MAD1L1 and SEC23B mutations were also identified in 2 of 101 cases of myeloproliferative neoplasms, but not in 42 healthy subjects. These findings challenge historic concepts of clonal evolution in CML.
我们在此报告首次使用全基因组测序（WGS）来研究一名慢性髓性白血病（CML）特殊患者的初始克隆动态。该患者以慢性期（CP）发病，其细胞存在双重标记的BCR-ABL1/JAK2突变，在9年时间里进展为加速期（AP），然后进入终末期急变期（BP）。WGS显示，诊断时的细胞还含有ASXL1、SEC23B、MAD1L1和RREB1的突变以及另外12000个罕见的DNA变异。对循环前体产生的内皮细胞进行WGS发现，其中许多变异与CML克隆共有。令人惊讶的是，对源自AP期细胞的诱导多能干细胞（iPSC）进行WGS仅发现另外6个编码体细胞突变，尽管造血后代保留了亲代AP期细胞水平的BCR-ABL1表达以及对伊马替尼和匹莫齐特的敏感性。对BP期细胞的有限分析显示，MAD1L1和RREB1变异独立亚克隆进展至纯合状态。在101例骨髓增殖性肿瘤患者中的2例也鉴定出了MAD1L1和SEC23B突变，但在42名健康受试者中未发现。这些发现挑战了CML克隆进化的传统概念。
