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V. Madan et al.
RUNX1 in AML, a disease with phenotypic and transcrip- tional profile reminiscent of t(8;21) AML.39,40
Discussion
This study, along with recent reports,5-10 provides a com- prehensive landscape of the mutational spectrum of t(8;21) AML, which is distinctive from other subtypes of AML and characterized by high frequency of alterations of KIT, ASXL2, DHX15 and MGA genes; and rare mutations
AB
of other commonly altered genes in myeloid leukemia (DNMT3A, RUNX1, IDH2, NPM1). Truncating mutations of ASXL2 occurred in 20% of newly-diagnosed t(8;21) AML cases, and were localized to exons 11 and 12, a pat- tern highly reminiscent of the mutational profile for ASXL1 in hematologic malignancies.41,42 However, unlike ASXL1, which is altered in a diverse range of hematologic diseases, mutations of ASXL2 are specific to the t(8;21) AML subtype. We also noted that the mutational frequen- cy of RAS pathway genes (NRAS and KRAS) and ZBTB7A in our Asian cohort of t(8;21) AML were notably lower
C
D
E
Figure 7. Gene expression changes in Asxl2-deficient LSK cells. (A and B) Changes in tran- script levels in LSK cells from >1- year old (A) and young (8-12- week old) (B) Asxl2 knockout (KO) versus wild-type (WT) litter- mates. For each age group and genotype, cells from 2 mice were analyzed. Genes significantly up- regulated in KO cells are repre- sented in red circles while down- regulated genes are shown in blue (FDR<0.1). (C) Venn dia- grams show overlap of genes either up-regulated or down-reg- ulated in young and old Asxl2 KO LSK cells compared with the WT cells from young and old mice, respectively. (D and E) GSEA comparing expression of genes in LSK cells from >1-year old WT and KO littermates for the select- ed gene sets (FDR<0.1): genes
up-regulated in hematopoietic progenitors by RUNX1-RUNX1T1 fusion (D), and genes down-regulated in hematopoietic progenitors in CBFA2T3 KO mice (E). NES: nor- malized enrichment score.
normal
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haematologica | 2018; 103(12)