Genetic characterization of patients with myeloid malignancies. Prevalence and role of ASXL1 gene mutations

Abstract

Molecular aberrations underlie the myeloid malignancies phenotype. We hypothesized that ASXL1 mutations could play an important role in the pathogenesis of these disorders. The prevalence of ASXL1 mutations in our cohort (n=640) was 18.2% in myelodysplastic syndromes (MDS), 38.5% in chronic myelomonocytic leukaemia (CMML), 8.4% in myeloproliferative neoplasms and 10.7% in acute myeloid leukaemia (AML). The distribution of mutations among disease subtypes suggested a role of ASXL1 mutations in disease progression. The majority of mutations were nonsense or frameshift, predicted to cause truncation of the protein upstream of important functional domains. Analysis of concurrent mutations showed that cytogenetically normal AML cases with ASXL1 mutations had significantly lower incidence of NPM1 and DNMT3A mutations than cases with wild type ASXL1. Next generation sequencing analysis of MDS cases with del(5q) showed that ASXL1 was among the most frequently mutated genes. ASXL1 mutations were often detected in cases with two or more mutations. Gene expression profiling of CD34+ cells from MDS/CMML patients suggested that cases with mutation of ASXL1 may have a different disease pathophysiology, possibly involving abnormalities in the retinoic acid receptor activation pathway. DNA methylation profiling of two series of CMML and MDS cases failed to detect a distinct profile associated to ASXL1 mutations, possibly caused by the presence of co-occurring mutations in genes with epigenetic role. Loss-of-function experiments in cultured normal ASXL1-deficient CD34+ cells resulted in impairment of terminal granulomonocytic differentiation and up-regulation of erythroid-related genes. This could suggest that the differentiation may be skewed towards the erythroid lineage.