Hematology Department, Hospital Clínico Universitario de Valencia, INCLIVA Research Institute, University of Valencia, Valencia, Spain.
Biochemistry and Molecular Pathology Department, Hospital Clínico Universitario de Valencia, INCLIVA Research Institute, Valencia, Spain.
Br J Haematol. 2021 Aug;194(4):708-717. doi: 10.1111/bjh.17675. Epub 2021 Jul 22.
In myelodysplastic syndromes (MDS), the 20q deletion [del(20q)] may cause deletion of the ASXL1 gene. We studied 153 patients with MDS and del(20q) to assess the incidence, prognostic value and impact on response to azacitidine (AZA) of ASXL1 chromosomal alterations and genetic mutations. Additionally, in vitro assay of the response to AZA in HAP1 (HAP1 ) and HAP1 ASXL1 knockout (HAP1 ) cells was performed. ASXL1 chromosomal alterations were detected in 44 patients (28·5%): 34 patients (22%) with a gene deletion (ASXL1 ) and 10 patients (6·5%) with additional gene copies. ASXL1 was associated with a lower platelet count. The most frequently mutated genes were U2AF1 (16%), ASXL1 (14%), SF3B1 (11%), TP53 (7%) and SRSF2 (6%). ASXL1 alteration due to chromosomal deletion or genetic mutation (ASXL1 /ASXL1 ) was linked by multivariable analysis with shorter overall survival [hazard ratio, (HR) 1·84; 95% confidence interval, (CI): 1·11-3·04; P = 0·018] and a higher rate for acute myeloid leukaemia progression (HR 2·47; 95% CI: 1·07-5·70, P = 0·034). ASXL1 /ASXL1 patients were correlated by univariable analysis with a worse response to AZA. HAP1 cells showed more resistance to AZA compared to HAP1 cells. In conclusion, ASXL1 alteration exerts a negative impact on MDS with del(20q) and could become useful for prognostic risk stratification and treatment decisions.
在骨髓增生异常综合征（MDS）中，20q 缺失[del(20q)]可能导致 ASXL1 基因缺失。我们研究了 153 例 MDS 伴 del(20q)患者，以评估 ASXL1 染色体改变和基因突变的发生率、预后价值以及对阿扎胞苷（AZA）反应的影响。此外，还在 HAP1（HAP1）和 HAP1 ASXL1 敲除（HAP1）细胞中进行了 AZA 反应的体外检测。在 44 例患者（28.5%）中检测到 ASXL1 染色体改变：34 例患者（22%）存在基因缺失（ASXL1），10 例患者（6.5%）存在额外基因拷贝。ASXL1 与血小板计数降低有关。最常突变的基因是 U2AF1（16%）、ASXL1（14%）、SF3B1（11%）、TP53（7%）和 SRSF2（6%）。多变量分析显示，染色体缺失或基因突变引起的 ASXL1 改变（ASXL1 /ASXL1）与总生存期缩短相关[风险比（HR）1.84；95%置信区间（CI）：1.11-3.04；P=0.018]，急性髓系白血病进展的发生率更高（HR 2.47；95%CI：1.07-5.70，P=0.034）。单变量分析显示，ASXL1 /ASXL1 患者对 AZA 的反应较差。与 HAP1 细胞相比，HAP1 细胞对 AZA 的耐药性更强。总之，ASXL1 改变对伴 del(20q)的 MDS 有负面影响，可能有助于进行预后风险分层和治疗决策。
