Annals of Hematology | 2019
ASXL2 mutation is recurrent in non-de novo AML1-ETO-negative acute myeloid leukemia
Abstract
Dear Editor, ASXL1, ASXL2, and ASXL3 compose the additional sex comb-like family, and they function as epigenetic regulators through recruitment of polycomb group repressor complexes (PRC). ASXL2 acts as a tumor suppressor in hematopoiesis [1–3]. ASXL2 deletion in hematopoietic stem cells (HSCs) leads to the development of myelodysplastic syndrome (MDS)-like disease or myeloid leukemia, and its mechanism is related to H3K27ac and H3K4me1/2 dysregulation [2]. ASXL1 mutation can be found in multiple spectra of myeloid malignancies, including various subtypes of acute myeloid leukemia (AML) [4]. Unlike ASXL1 mutation, ASXL2 mutation is largely restricted to AML1-ETO positive AML [5–10]. It has been demonstrated that ASXL2 target genes strongly overlap with those of RUNX1 and AML1-ETO, and the loss of ASXL2 promotes leukemogenesis via increasing chromatin accessibility at putative enhancers of key leukemogenic loci [1]. However, the status and frequency of ASXL2 mutation in AML1-ETO-negative AML remained largely unknown. Between May 2018 and March 2019, 85 AML patients were enrolled in this study, and then submitted to targeted exome-sequence in our center, while acute promyelocytic leukemia patients were excluded. In our cohort, male/female was 38/47, and the median age was 51 (range 13–81). When the samples were collected, 1 case was diagnosed as bonemarrow (BM) infiltrated myeloid sarcoma (MS), 4 were MDS transformed AML (MDS/AML), 3 were mixed lineage leukemia (MLL), 5 were refractory or relapsed (r/r) AML, and other 72 were de novo AML (Fig. 1a). ASXL1 and ASXL2 mutations were both analyzed for our patients, and 10/85 were positive for one of them. Interestingly, 3/4 MDS/AML patients in our study accompanied with ASXL1 or ASXL2 mutation, indicating their important roles in transformation from MDS to AML. We analyzed our 6 ASXL2 mutated AML patients in detail and found that ASXL2 mutated de novo AML was all positive for AML1ETO; however, other ASXL2 mutated AML belonged to non-de novo AML and they all were negative for AML1ETO in our study, indicating the specific distribution of ASXL2 mutation in AML (Fig. 1b). Therefore, ASXL2 mutation was also frequent in AML1-ETO-negative AML, especially non-de novo AML. Interestingly, ASXL2 mutation cooccurred with BCR-ABL1 in case no. 8 besides ofAML1-ETO. ASXL2mutation was reported mutually exclusive with ASXL1 mutation, CBFβ-MYH11, and RUNX1 mutation [5, 6, 8]. However, it was not absolute and ASXL2 and RUNX1 mutations co-occurred in our case no. 9 (Fig. 1c). In AML1-ETO-positive AML, ASXL2 mutation mainly affected its exons 11 and 12, and frame-shift or nonsense mutations were most common [5]. In our 6 ASXL2 mutated cases, the mutation sites of 5 cases were located at exon 11, while of 1 case at exon 12. Furthermore, frame-shift mutation accounted 83.3% (5/6) and nonsense mutation only occurred in 1 case. Therefore, those mutations generated pre-mature termination of ASXL2 and led to its haploidinsufficiency at least. However, whether truncated ASXL2 played a dominated negative role on the wild type (WT) of ASXL2, as ASXL1 mutation (p.G646Wfs) [4], the most common mutational type in myeloid malignancy, did on ASXL1 WT, remained unknown. Collectively, ASXL2 mutation could also affect non-de novo AML1-ETO-negative AML. * Jie Jin [email protected]