Introduction: With the development of next generation sequencing (NGS), the interrelation between genetic and epigenetic abnormality in myeloid malignancies has attracted significant attention. Clinical reports provide strong evidence that while the specific gene mutations are the initial event for the myeloid malignancies, the concomitant gene mutations contribute to the disease progression. Although ASXL1 mutations have been found in myeloid malignancies, the impact of co-mutation with ASXL1 on the disease progression remains largely unknown. In the current study, we aim to investigate the clinical significance of the association between ASXL1 mutations and a spectrum of gene mutations in a large cohort of patients with myeloid malignancies.

Methods: Targeted sequencing including 112 hematopoietic malignancy-related genes was used to analyze the gene mutations in patients with ASXL1 mutations. The impact of gene mutations on clinical characteristics and prognosis was further analyzed. The correlation between clinical/laboratory features and the gene mutations was performed by the χ2 test, and differences in values and in ranks were assessed by Student t-tests. Overall survival rate was assessed by the Kaplan-Meier method and calculated by the Log-rank test.

Results: A cohort of 138 myeloid malignant patients harboring ASXL1 mutations was recruited to the current study, including patients with myelodysplastic syndromes (MDS) (37.68%, n = 52), myeloproliferative neoplasms (MPN) (21.01%, n = 29), myelodysplastic/myeloproliferative neoplasms (MDS/MPN) (7.25%, n = 10), and acute myeloid leukemia (AML) (34.06%, n = 47). In addition, to ASXL1 mutations, 89 genes were mutated in these patients, and 96.4% (133) of the patients were accompanied by at least one gene mutation. Among those mutated genes, 55.8% (77/138) was epigenetic genes, 65.9% (91/138) was signal transduction pathway genes, 28.2% (39/138) was spliceosome related genes, 36.9% (51/138) was transcription factor genes, and 18.8% (26/138) was cell cycle and apoptosis related genes. The most common co-mutated genes were RAS pathway related genes (25.4%, 35/138) and SETBP1 (21.7%, 30/138). Patients with ASXL1 and RAS pathway co-mutations (ASXL1mutRASmut) had significantly lower levels of hemoglobin and platelets compared to ASXL1 mutated patients without RAS pathway mutation (ASXL1mutRASwt) (hemoglobin 81 (33-152) g/L vs. 96 (18-195) g/L, P=0.012; and platelets (51 (8-695)×109/L vs. 75 (3-3149) × 109/L, P=0.032, respectively). Importantly, MDS patients with ASXL1mutRASmut were more likely to be associated with high International Prognostic Scoring System (IPSS) scores (P=0.016). Moreover, the median survival time of these ASXL1mutRASmut patients (mean = 17 months, 1-35 months) was significantly shorter than that of ASXL1mutRASwtpatients (mean = 21 months, 2-75 months) (P=0.031).

Conclusions: Our study provides a comprehensive overview of the association between the clinical features and prognosis with genes co-mutated with ASXL1 in patients with myeloid malignancies. We conclude that concomitant mutations of ASXL1 with RAS pathway genes associate with high risk of myeloid transformation and lower overall survival rates.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.