ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia

Abstract

Additional sex combs-like (ASXL) proteins are mammalian homologues of additional sex combs (Asx), a regulator of trithorax and polycomb function in Drosophila. While there has been great interest in ASXL1 due to its frequent mutation in leukemia, little is known about its paralog ASXL2, which is frequently mutated in acute myeloid leukemia patients bearing the RUNX1-RUNX1T1 (AML1-ETO) fusion. Here we report that ASXL2 is required for normal haematopoiesis with distinct, non-overlapping effects from ASXL1 and acts as a haploinsufficient tumour suppressor. While Asxl2 was required for normal haematopoietic stem cell self-renewal, Asxl2 loss promoted AML1-ETO leukemogenesis. Moreover, ASXL2 target genes strongly overlapped with those of RUNX1 and AML1-ETO and ASXL2 loss was associated with increased chromatin accessibility at putative enhancers of key leukemogenic loci. These data reveal that Asxl2 is a critical regulator of haematopoiesis and mediates transcriptional effects that promote leukemogenesis driven by AML1-ETO.

Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation

“…Antibodies used for ChIP include anti-H3K4me3 (9751S; Cell Signaling), anti-H3K27me3 (07-449; Millipore), anti-H2AK119Ub (8240; Cell Signaling), anti-Asxl1 (sc-85283; Santa Cruz Biotechnology), and anti-FLAG (F1804; Sigma-Aldrich). ChIP assays were processed and barcoded library and raw data analyses were performed as previously described ( Micol et al, 2017 ).…”

Transcriptome-wide analysis uncovers the targets of the RNA-binding protein MSI2 and effects of MSI2's RNA-binding activity on IL-6 signaling

“…Another target, EGR1, was shown to be often deregulated in hematological malignancies such as AML, CML, multiple myelomas and B cell lymphomas (22). ASXL2, another target of MSI2 is a tumor suppressor which maintains normal HSC function (23,24). The functional link between MSI2 and these targets gives us a better idea about the role of MSI2 in hematopoiesis and leukemia.…”

A bidentate Polycomb Repressive-Deubiquitinase complex is required for efficient activity on nucleosomes

“…The Drosophila ASX protein has three human orthologs (ASXL1–3), which also possess an N-terminal Deubad and a C-terminal plant homeodomain (PHD). Truncating mutations in ASXL1 and ASXL2 that remove the PHD, but retain the Deubad, have been linked to both myeloid and myelomonocytic leukaemias 21 , 22 , 35 , as well as Bohring–Opitz syndrome 36 . In recently published work, Sahtoe et al 9 and Peng et al 18 investigated a conserved ‘NEF’ region in the Deubad domain of ASX-like proteins (residues Asn283–Glu284–Phe285 in ASX) (Supplementary Fig.…”