3.0
ASXL1 in AML
Pathway ID: SIGNOR-AML-ASXL1
Description: Additional sex combs-like 1 (ASXL1) is a member of the ASXL family and is involved in epigenetic regulation. ASXL mutations in AML are predominantly frameshift and nonsense mutations generating C-terminally truncated proteins, and are associated with a poor prognosis. The N-terminal ASXH domain mediates interaction with a nuclear ubiquitin carboxy-terminal hydrolase, BAP1. BAP1 is an essential component of the “polycomb repressive deubiquinase complex” (PR-DUB), which leads to gene repression. How ASXL1 mutations, mostly heterozygous somatic mutation, induce myeloid transformation is not fully understood. ASXL1 gene may act as a aploinsufficient or dominant negative tumor suppressor, since loss of ASXL1 function (in promoting H3K27me3) contributes to myeloid transformation and ASXL1 is specifically required for the increased expression of p15(INK4B), in response to oncogenic signaling. On the other hand, cancer-associated ASXL1 mutations aberrantly enhance BAP1. This hyperactive mutant ASXL1/BAP1 complex induces upregulation of posterior HOXA genes and IRF8, thus impairing multilineage differentiation of haematopoietic progenitors. (PMID: 30013160; PMID: 26470845)
Curated by: irozzo
Description: Additional sex combs-like 1 (ASXL1) is a member of the ASXL family and is involved in epigenetic regulation. ASXL mutations in AML are predominantly frameshift and nonsense mutations generating C-terminally truncated proteins, and are associated with a poor prognosis. The N-terminal ASXH domain mediates interaction with a nuclear ubiquitin carboxy-terminal hydrolase, BAP1. BAP1 is an essential component of the “polycomb repressive deubiquinase complex” (PR-DUB), which leads to gene repression. How ASXL1 mutations, mostly heterozygous somatic mutation, induce myeloid transformation is not fully understood. ASXL1 gene may act as a aploinsufficient or dominant negative tumor suppressor, since loss of ASXL1 function (in promoting H3K27me3) contributes to myeloid transformation and ASXL1 is specifically required for the increased expression of p15(INK4B), in response to oncogenic signaling. On the other hand, cancer-associated ASXL1 mutations aberrantly enhance BAP1. This hyperactive mutant ASXL1/BAP1 complex induces upregulation of posterior HOXA genes and IRF8, thus impairing multilineage differentiation of haematopoietic progenitors. (PMID: 30013160; PMID: 26470845)
Curated by: irozzo
