Yamato Genki, Shiba Norio, Yoshida Kenichi, Shiraishi Yuichi, Hara Yusuke, Ohki Kentaro, Okubo Jun, Okuno Haruna, Chiba Kenichi, Tanaka Hiroko, Kinoshita Akitoshi, Moritake Hiroshi, Kiyokawa Nobutaka, Tomizawa Daisuke, Park Myoung-Ja, Sotomatsu Manabu, Taga Takashi, Adachi Souichi, Tawa Akio, Horibe Keizo, Arakawa Hirokazu, Miyano Satoru, Ogawa Seishi, Hayashi Yasuhide
Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan.
Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan.
Genes Chromosomes Cancer. 2017 May;56(5):382-393. doi: 10.1002/gcc.22443. Epub 2017 Feb 14.
ASXL2 is an epigenetic regulator involved in polycomb repressive complex regulation or recruitment. Clinical features of pediatric acute myeloid leukemia (AML) patients with ASXL2 mutations remain unclear. Thus, we investigated frequencies of ASXL1 and ASXL2 mutations, clinical features of patients with these mutations, correlations of these mutations with other genetic alterations including BCOR/BCORL1 and cohesin complex component genes, and prognostic impact of these mutations in 369 pediatric patients with de novo AML (0-17 years). We identified 9 (2.4%) ASXL1 and 17 (4.6%) ASXL2 mutations in 25 patients. These mutations were more common in patients with t(8;21)(q22;q22)/RUNX1-RUNX1T1 (ASXL1, 6/9, 67%, P = 0.02; ASXL2, 10/17, 59%, P = 0.01). Among these 25 patients, 4 (27%) of 15 patients with t(8;21) and 6 (60%) of 10 patients without t(8;21) relapsed. However, most patients with relapse were rescued using stem cell transplantation irrespective of t(8;21). The overall survival (OS) and event-free survival (EFS) rates showed no differences among pediatric AML patients with t(8;21) and ASXL1 or ASXL2 mutations and ASXL wild-type (5-year OS, 75% vs. 100% vs. 91% and 5-year EFS, 67% vs. 80% vs. 67%). In 106 patients with t(8;21) AML, the coexistence of mutations in tyrosine kinase pathways and chromatin modifiers and/or cohesin complex component genes had no effect on prognosis. These results suggest that ASXL1 and ASXL2 mutations play key roles as cooperating mutations that induce leukemogenesis, particularly in pediatric AML patients with t(8;21), and these mutations might be associated with a better prognosis than that reported previously.
ASXL2是一种参与多梳抑制复合物调控或募集的表观遗传调节因子。ASXL2突变的小儿急性髓系白血病（AML）患者的临床特征仍不清楚。因此，我们调查了369例0至17岁初发AML小儿患者中ASXL1和ASXL2突变的频率、这些突变患者的临床特征、这些突变与包括BCOR/BCORL1和黏连蛋白复合物组成基因在内的其他基因改变的相关性，以及这些突变对预后的影响。我们在25例患者中鉴定出9例（2.4%）ASXL1突变和17例（4.6%）ASXL2突变。这些突变在t(8;21)(q22;q22)/RUNX1-RUNX1T1患者中更为常见（ASXL1，6/9，67%，P = 0.02；ASXL2，10/17，59%，P = 0.01）。在这25例患者中，15例t(8;21)患者中有4例（27%）复发，10例无t(8;21)患者中有6例（60%）复发。然而，大多数复发患者通过干细胞移植得到挽救，无论是否有t(8;21)。t(8;21)且有ASXL1或ASXL2突变的小儿AML患者与ASXL野生型患者的总生存（OS）率和无事件生存（EFS）率无差异（5年OS，75%对100%对91%；5年EFS，67%对80%对67%）。在106例t(8;21) AML患者中，酪氨酸激酶途径和染色质修饰因子及/或黏连蛋白复合物组成基因的突变共存对预后无影响。这些结果表明，ASXL1和ASXL2突变作为协同突变在诱导白血病发生中起关键作用，尤其是在t(8;21)的小儿AML患者中，并且这些突变可能与比先前报道更好的预后相关。
