Incidence and prognostic impact of ASXL2 mutations in adult acute myeloid leukemia patients with t(8;21)(q22;q22): a study of the German-Austrian AML Study Group-猫眼课题宝

DOI：

10.1038/leu.2017.18

发表时间：

2017-01

期刊：

Leukemia

影响因子：

11.4

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

Nikolaus Jahn;M. Agrawal;L. Bullinger;D. Weber;A. Corbacioglu;V. Gaidzik;L. Schmalbrock;F. Thol;M. Heuser;J. Krauter;G. Göhring;Andrea Kündgen;Walter Fiedler;M. Wattad;Gerhard Held;C.-H. Köhne;Heinz-August Horst;M. Lübbert;A. Ganser;R. Schlenk;Hartmut Döhner;K. Döhner;P. Paschka

t（8; 21）（q22; q22）/RUNX 1/RUNX 1 T1的急性髓性白血病（AML）被归类为WHO类别“AML伴复发性遗传异常”中的一个独特实体。1 RUNX 1/RUNX 1 T1融合体构成了白血病前状态，但额外的协同遗传事件对于诱导白血病表型是必要的。2虽然t（8; 21）AML被认为是一个有利的AML亚群，但只有约50%的患者可以在强化治疗后治愈。3，4全面的遗传特征可能有助于更好地理解疾病生物学和诊断，以及开发新的治疗方法。大约一半的t（8; 21）AML患者携带其他基因突变，其中KIT、NRAS、FLT 3和ASXL 1代表最常见的突变基因。5在儿童核心结合因子（CBF）AML中首次发现了ASXL 2（额外性梳样2）的复发突变。6迄今为止，ASXL 2在正常造血中的作用以及ASXL 2突变对恶性转化的潜在贡献尚未确定。值得注意的是，ASXL 2与paradox ASXL 1具有高度的氨基酸同源性，paradox ASXL 1是一种参与转录调控的表观遗传修饰剂，在骨髓恶性肿瘤中经常发生突变。7- 9在Micol等人对170例CBF-AML儿童或成人患者的研究中（t（8; 21），n= 110; inv（16），n= 60），在22.7%的病例中检测到ASXL 2突变，并且仅在t（8; 21）阳性AML组中发现，这意味着突变ASXL 2在该AML亚组的白血病发生中起作用。10最近，我们进行了一项高通量测序研究，包括儿童（n= 87）和成人（n= 78）CBF-AML患者，以全面评估基因组格局，并深入了解CBF-AML的生物学。11基于本研究中额外的分子畸变模式，我们可以证明t（8; 21）和inv（16）AML是不同的生物实体。值得注意的是，我们还可以证实ASXL 2突变的高发生率及其对t（8; 21）阳性AML的排他性（18.8%，n= 16/85）。[11]一项初步分析包括了总共39名t（8; 21）阳性AML成人患者（ASXL 2突变型n= 7; ASXL 2野生型n= 32），未发现突变型ASXL 2的任何相关预后影响，但显然这种过早的分析受到病例数量少的阻碍。11

Acute myeloid leukemia (AML) with t (8; 21)(q22; q22)/RUNX1/RUNX1T1 is categorized as a distinct entity within the WHO category ‘AML with recurrent genetic abnormalities’. 1 The RUNX1/RUNX1T1 fusion constitutes a pre-leukemic condition, but additional co-operating genetic events are necessary to induce a leukemic phenotype. 2 Although AML with t (8; 21) is considered as a favorable AML subset, only~ 50% of patients can be cured following intensive treatment. 3, 4 Comprehensive genetic characterization might contribute to a better understanding of the disease biology and prognostication, as well as to the development of novel treatment approaches. Approximately half of the patients with t (8; 21) AML harbor additional gene mutations, with KIT, NRAS, FLT3 and ASXL1 representing the most frequently mutated genes. 5 Recurrent mutations in ASXL2 (additional sex combs-like 2) were first identified in pediatric core-binding factor (CBF) AML. 6 To date, the role of ASXL2 in normal hematopoiesis and the potential contribution of ASXL2 mutations to malignant transformation have not been defined. Of note, ASXL2 shares a high-degree amino-acid homology with the paralog ASXL1, an epigenetic modifier involved in transcriptional regulation, which is frequently mutated in myeloid malignancies. 7–9In a study by Micol et al. on 170 pediatric or adult patients with CBF-AML (t (8; 21), n= 110; inv (16), n= 60) ASXL2 mutations were detected in 22.7% of the cases, and they were exclusively found within the group of t (8; 21)-positive AML, implying a role for mutant ASXL2 in leukemogenesis of this AML subset. 10 More recently, we conducted a high-throughput sequencing study including pediatric (n= 87) and adult (n= 78) patients with CBF-AML to assess the genomic landscape in a comprehensive manner and to gain insights into the biology of CBF-AML. 11 Based on the pattern of additional molecular aberrations in this study we could show that AML with t (8; 21) and inv (16) are distinct biologic entities. Of note, we also could confirm the high incidence of ASXL2 mutations and their exclusiveness to t (8; 21)-positive AML (18.8%, n= 16/85). 11 A preliminary analysis including a total of 39 adult patients with t (8; 21)-positive AML (ASXL2 mutated n= 7; ASXL2 wild type n= 32) did not reveal any relevant prognostic impact of mutant ASXL2, but obviously this premature analysis was hampered by the low number of cases. 11

Incidence and prognostic impact of ASXL2 mutations in adult acute myeloid leukemia patients with t(8;21)(q22;q22): a study of the German-Austrian AML Study Group

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