Myelodysplastic syndromes with 20q deletion: incidence, prognostic value and impact on response to azacitidine of ASXL1 chromosomal deletion and genetic mutations

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(WT)) and HAP1 ASXL1 knockout (HAP1(KN)) cells was performed. ASXL1 chromosomal alterations were detected in 44 patients (28 center dot 5%): 34 patients (22%) with a gene deletion (ASXL1(DEL)) and 10 patients (6 center dot 5%) with additional gene copies. ASXL1(DEL) 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(DEL)/ASXL1(MUT)) was linked by multivariable analysis with shorter overall survival [hazard ratio, (HR) 1 center dot 84; 95% confidence interval, (CI): 1 center dot 11-3 center dot 04; P = 0 center dot 018] and a higher rate for acute myeloid leukaemia progression (HR 2 center dot 47; 95% CI: 1 center dot 07-5 center dot 70, P = 0 center dot 034). ASXL1(DEL)/ASXL1(MUT) patients were correlated by univariable analysis with a worse response to AZA. HAP1(KN) cells showed more resistance to AZA compared to HAP1(WT) 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.