Aberrant histone modifications induced by mutant ASXL1 in myeloid neoplasms

Abstract

An epigenetic modulator Additional sex combs-like 1 (ASXL1) is recurrently mutated in myeloid neoplasms such as myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs). ASXL1 mutations are also frequently detected in clonal hematopoiesis with indeterminate potential (CHIP), which is the clonal expansion of premalignant hematopoietic cells without any evidence of hematological malignancies. Thus, understanding the roles of ASXL1 in hematopoiesis and myeloid neoplasms is a clinically crucial issue. ASXL1 mutations in hematological neoplasms are typically frameshift or nonsense mutations and occur near the 5′ end of the last exon, thereby the transcripts would escape from nonsense-mediated decay, Indeed, we identified the C-terminally truncated mutant protein of ASXL1 in several cell lines derived from patients with myeloid leukemia. In mouse models, expression of the mutant ASXL1 results in impaired hematopoiesis and promotes development of myeloid neoplasms. In addition, recent findings from biochemical analysis have demonstrated that the mutant ASXL1 protein gains new functions including enhancing catalytic activity of BRCA1-associated protein 1 (BAP1), resulting in reduction of H2AK119ub and aberrant gene expression essential for myeloid transformation. In this review, we will focus on the pivotal roles of the mutant ASXL1 on histone modifications and myeloid transformation.

The genetics of myelodysplastic syndromes and the opportunities for tailored treatments

“…These findings indicate that wild-type ASXL1 is a major tumor suppressor in hematopoiesis and suggest loss-of-function features of ASXL1 mutations ( 132 ). ASXL1 wild-type protein can also support H3K4 methylation through O-linked N-acetylglucosamine transferase (OGT) ( 44 ), H2AK119 ubiquitination through PRC1, and H3K27 methylation in specific loci. Mutations in ASXL1 were originally identified in MDS with del20q11 ( 133 ).…”

ASXL1/2 mutations and myeloid malignancies

“…BAP1-ASXL2, but not ASXL1-BAP1 complexes, appears to mediate this tumor-suppressive function; overexpression of BAP1 or ASXL2, but not ASXL1, induces senescence, and deletion of the ASXM domain of ASXL2 impairs senescence (human fibroblasts IMR90 cell line) [ 99 ]. While hematopoietic-restricted BAP1 loss in mice has been reported to lead to myeloproliferative [ 103 ] or MDS-like disease [ 104 ], somatic BAP1 mutations, unlike in some solid tumors (e.g., malignant mesothelioma and melanoma), are rarely present in myeloid malignancies [ 105 ]. Indeed, Dey et al reported that out of 32 patients with de novo MDS, a somatic BAP1 mutation was detected in one case [ 104 ].…”

Genetic Landscape of Myeloproliferative Neoplasms with an Emphasis on Molecular Diagnostic Laboratory Testing

“…Within the histone modifiers, two frequently mutated genes have been identified in PMF: ASXL1 and EZH2. ASXL1 or additional sex combs-like 1, interacts with Polycomb group complexes (PgC), which are involved in histone modifications to continue gene expression [46,133,134]. Many studies have shown the importance of ASXL1 in normal hematopoiesis, but along with TET2, this gene is the second most common to be implicated in MPNs [46].…”