Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network

Abstract

Additional sex combs-like 1 (ASXL1) interacts with BRCA1-associated protein 1 (BAP1) deubiquitinase to oppose the polycomb repressive complex 1 (PRC1)mediated histone H2A ubiquitylation. Germline BAP1 mutations are found in a spectrum of human malignancies, while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis. Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region, resulting in the production of C-terminally truncated mutant ASXL1 proteins. How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogenesis are unclear. Here, we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes. We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells, and lose the ability to interact with FOXK1/K2. Specific deletion of the mutant allele eliminates the expression of C-terminally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1, thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes,

Prognostic value of ASXL1 mutations in patients with primary myelofibrosis and its relationship with clinical features: a meta-analysis

“…ASXL1 mutations alter the epigenome of hematopoietic stem cells (HSC) and increase the susceptibility to leukemia transformation [42]. In hematological malignancies, C-terminally truncated ASXL1 mutant protein significantly weakens the transcriptional regulation of BAP1-ASXL1-FOXK1 / K2 complex, downregulates the expression of multiple tumor suppressor genes, and then regulates glucose metabolism, hypoxia perception, JAK-STAT, and other tumor-related signaling pathways, promoting proliferation and self-renewal of leukemia cells [43]. Therefore, ASXL1 mutations may play an important role in the pathogenesis and transformation of PMF.…”

Mechanisms of Polycomb group protein function in cancer

“… 140 Conversely, disruption of its chromatin recruitment or catalytic activity could result in an increase in H2AK119ub and H3K27me3. 146 , 150 Depending on the genes targeted, this might switch the transcriptional state of oncogenes or tumor suppressor genes.…”

The Functions and Mechanisms of PR-DUB in Malignancy

“…Notably the expression of C-terminal truncation of ASXL1 has been observed in a few leukemia cell lines (Balasubramani et al, 2015;Xia et al, 2020). Moreover, artificial or transgenic overexpression of ASXL1 C-terminal truncated mutants leads to gain of H2AK119 deubiquitylation activity and facilitates myeloid transformation (Inoue et al, 2013;Balasubramani et al, 2015;Asada et al, 2018;Nagase et al, 2018;Yang et al, 2018;Xia et al, 2020). Besides, ASXL1 mutant may synergize with hematopoietically expressed homeobox (HHEX) to promote myeloid transformation.…”