Deregulation of tumor suppressive ASXL1−PTEN/AKT axis in myeloid malignancies

Abstract

Mutations of epigenetic regulators are pervasive in human tumors. ASXL1 is frequently mutated in myeloid malignancies. We previously found that ASXL1 forms together with BAP1 a complex that can deubiquitinylate mono-ubiquitinylated lysine 119 on Histone H2A (H2AK119ub1), a Polycomb repressive mark. However, a complete mechanistic understanding of ASXL1 in transcriptional regulation and tumor suppression remains to be defined. Here we find that depletion of Asxl1 confers murine 32D cells to IL3-independent growth at least partly due to sustained activation of PI3K/AKT signaling. Consistently, Asxl1 is critical for the transcriptional activation of Pten, a key negative regulator of AKT activity. Then we confirm that Asxl1 is specifically enriched and required for H2AK119 deubiquitylation at the Pten promoter. Interestingly, ASXL1 and PTEN expression levels are positively correlated in human blood cells and ASXL1 mutations are associated with lower expression levels of PTEN in human myeloid malignancies. Furthermore, malignant cells with ASXL1 downregulation or mutations exhibit higher sensitivity to the AKT inhibitor MK2206. Collectively, this study has linked the PTEN/AKT signaling axis to deregulated epigenetic changes in myeloid malignancies. It also provides a rationale for mechanism-based therapy for patients with ASXL1 mutations.

Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway

“…Thus, these findings revealed a function of ASXL1-MT as a signaling modulator beyond its known roles as an epigenetic regulator. On the other hand, one recent study has shown that Asxl1 loss activates Akt/mTOR pathway due to an epigenetic dysregulation at the Pten locus 65 . Thus, we cannot completely exclude the possibility that ASXL1-MT activates Akt/mTOR pathway through an epigenetic-dependent manner as well.…”

The Functions and Mechanisms of PR-DUB in Malignancy

“…And we have demonstrated that ASXL1 is driven to erase H2AK119ub1 for transcription induction. Loss of ASXL1 leads to the retention of H2AK119ub1 at the regulatory loci of INK4B and PTEN and thereby the inactivation of these two well-known tumor suppressor genes in response to oncogenic signals, supporting ASXL1 as a tumor suppressor ( Wu et al, 2015 ; Cao et al, 2020 ).…”

Analysis of 5-Azacytidine Resistance Models Reveals a Set of Targetable Pathways

“…Similarly, PI3K p110δ isoform level followed the same pattern of association in myeloblasts of progressing MDS patients [ 30 ]. Another paper recently showed that ASXL1 mutations, which are often associated with lower PTEN levels, exhibit significantly higher sensitivity to the AKT inhibitor MK2206, consistent with the fact that excessive PI3K/AKT/mTOR activation may be a direct consequence of HMAs targeting the general mechanism of transcriptional repression (hence protection of chromatin structure) as well as AML cell survival [ 31 ].…”

“…This signaling pathway is often dysregulated in resistant cells to various antileukemic agents [ 32 ]. However, the use of SOR in AML patients is quite effective, especially in patients with FLT3-ITD mutation [ 33 ], leading to prolonged survival [ 31 ], again reinforcing the importance of the RAS/RAF/MEK/ERK signaling pathway. Regarding signaling through a family of different Src kinases (including LYN and SRC), these are expressed in AML and their phosphorylation regulates leukemia cell proliferation and survival (including through LYN mediating mTOR activation) [ 34 ].…”