ASXL genes and RUNX1: an intimate connection?

Abstract

In this issue of Blood, Micol et al report the discovery of mutations in the additional sex combs-like 2 (ASXL2) gene in about one-quarter of acute myeloid leukemia (AML) patients carrying the t(8;21) translocation. Based on this rationale, Micol et al performed whole-exome sequencing of 3 patients with t(8;21) AML, and identified 2 somatic mutations in the ASXL2 gene. In a validation cohort of 110 adult and pediatric patients with t(8;21), ASXL2 mutations were present in 23%, making ASXL2 the secondmost commonly mutated gene in this cytogenetic subgroup, behind KIT (see figure). ASXL2 mutations have previously been reported, although at a much lower frequency, in various solid tumors including cancers of the bladder, prostate, endometrium, pancreas, and breast. Recently, Huether and colleagues studied 1000 pediatric cancer genomes and found ASXL2 mutations in 7 patients, including 6 with AML and balanced chromosomal rearrangements affecting the core binding factor (CBF) genes.3 Micol and colleagues now extend this initial report by demonstrating that ASXL2 mutations are restricted to patients with the t(8;21) translocation, which leads to a RUNX1-RUNX1T1 gene fusion. In contrast, ASXL2 mutations were absent in patients with RUNX1 point mutations or in patients with inversion inv(16), causing rearrangement of the RUNX1 heterodimerization partner CBF b (CBFB). ASXL1 mutations were found in 10% of t(8;21) patients, and were mutually exclusive with ASXL2 mutations. Micol et al also investigated the prognostic relevance of ASXL gene mutations in t(8;21) AML. They observed no difference in overall survival between ASXL1-mutated, ASXL2-mutated, and wild-type patients (see figure). Cumulative incidence of relapse appeared to be higher in patients with ASXL1 or ASXL2 mutations, but this difference did not achieve statistical significance. These results are consistent with a previous study reporting that 11.5% of adult t(8;21) AML patients carry ASXL1 mutations, and that ASXL1-mutated patients have significantly shorter event-free survival, but similar overall survival compared with those with wild-type ASXL1.4 Of note, we and others have found that ASXL1 gene mutations associate with

Next-Generation Sequencing Improves Diagnosis, Prognosis and Clinical Management of Myeloid Neoplasms

“…A total of 278 pathogenic variants were detected in 39 genes in 121 cases of MN. The number of genes altered and the most frequent variants in mutated genes in MN (also mutated genes by functional group), and the gene co-occurrences and mutual exclusivity were in accordance with previously results described in the literature [9,10,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42]. In the case of MPN, there is a low percentage of patients carrying gene variants and the median number of variants per patient is low as well.…”

Comprehensive mutational profiling of core binding factor acute myeloid leukemia

“…19,20 Interestingly, ASXL2 mutations are not recurrent in subsets of AML other than t(8;21) AML, suggesting an important potential functional intersection between ASXL2 mutations and the RUNX1-RUNX1T1 fusion specifically. 21 Besides ASXL1/2 mutations, however, no other recurrent mutations specific to 1 or both CBF AML subsets are currently known.…”

Focusing on frequent ASXL1 mutations in myeloid neoplasms, and considering rarer ASXL2 and ASXL3 mutations

“…Overall ASXL1 mutations are much more common and seen in wide range of myeloid neoplasms as comprehensively reviewed by Alvarez-Argote et al, while current studies show only a single case of ASXL2 mutation in CMML and no ASXL3 mutations in MDS or MPN (Table 1) 15 . In fact, ASXL2 mutations are documented almost exclusively in AML with t(8;21)(q22;q22);RUNX1-RUNX1T1 and may be functionally linked to the RUNX1-RUNX1T1 gene fusion, since ASXL2 mutations and RUNX1 point mutation or inversion of chromosome 16 are mutually exclusive 16 . In some respects this is similar to ASXL1 where mutations are seen in AML with t(8;21)(q22;q22);RUNX1-RUNX1T1 but not in AML with inv(16)(p13q22);CBFB-MYH11; however, dissimilar to ASXL2, ASXL1 mutations may be associated with RUNX1…”