Chromatin regulator Asxl1 loss and Nf1 haploinsufficiency cooperate to accelerate myeloid malignancy

Abstract

ASXL1 is frequently mutated in myeloid malignancies and is known to co-occur with other gene mutations. However, the molecular mechanisms underlying the leukemogenesis associated with ASXL1 and cooperating mutations remain to be elucidated. Here, we report that Asxl1 loss cooperated with haploinsufficiency of Nf1, a negative regulator of the RAS signaling pathway, to accelerate the development of myeloid leukemia in mice. Loss of Asxl1 and Nf1 in hematopoietic stem and progenitor cells resulted in a gain-of-function transcriptional activation of multiple pathways such as MYC, NRAS, and BRD4 that are critical for leukemogenesis. The hyperactive MYC and BRD9 transcription programs were correlated with elevated H3K4 trimethylation at the promoter regions of genes involving these pathways. Furthermore, pharmacological inhibition of both the MAPK pathway and BET bromodomain prevented leukemia initiation and inhibited disease progression in Asxl1Δ/Δ Nf1Δ/Δ mice. Concomitant mutations of ASXL1 and RAS pathway genes were associated with aggressive progression of myeloid malignancies in patients. This study sheds light on the effect of cooperation between epigenetic alterations and signaling pathways on accelerating the progression of myeloid malignancies and provides a rational therapeutic strategy for the treatment of myeloid malignancies with ASXL1 and RAS pathway gene mutations.

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

“…Therefore, it provides a rationale for mechanism-based therapy in patients with genetic or even epigenetic lesions of ASXL1 . Given that mutations of ASXL1 and RAS ( Abdel-Wahab et al, 2012 ) or NF1 ( Zhang et al, 2018b ) often co-occur in myeloid malignancies, it is tempting to generate more relevant models for the understanding of pathophysiological mechanisms and to test potential combination therapies.…”

“…Recently, two independent groups have reported that the constitutive or conditional deletion of Asxl1 in the hematopoietic system in mice leads to the development of MDS-like defects, including dysplastic neutrophils and cytopenias, which may transform into myeloid leukemia with age ( Abdel-Wahab et al, 2013 ; Wang et al, 2014 ). Using genetic models, Asxl1 loss collaborates with oncogenic NRasG12D mutation ( Abdel-Wahab et al, 2012 ; Wu et al, 2015 ) or haploinsufficiency of Nf1 ( Zhang et al, 2018b ) in bone marrow cells to induce myeloid malignancies. These studies suggest that ASXL1 mutations may function as an early/initiating event in the development of myeloid malignancies, and additional genetic events may cooperate with Asxl1 loss to induce leukemia.…”

The Functions and Mechanisms of PR-DUB in Malignancy

“…Consistent with the clinical prognosis ( Cui et al, 2015 , 2016 ), hematopoietic-specific deletion of both Asxl1 and Tet2 leads to a much earlier onset of MDS than the deletion of Asxl1 or Tet2 alone. In support, Asxl1 deficiency accompanied with haploinsufficiency of Nf1 or KRas oncogenic mutation accelerates the development of myeloid leukemia in mice ( Abdel-Wahab et al, 2012 ; Zhang et al, 2018 ). Therefore, these models argue that loss of ASXL1 contributes to the initiation and progression of myeloid malignancies, dependent or independent of its H2AK119 deubiquitylation activity.…”

Oncogenic truncations of ASXL1 enhance a motif for BRD4 ET-domain binding

“…Our finding that ASXL1 drives BRD4 co-localization with the MAZ transcription could be particularly relevant in this regard. For instance, MAZ has: a known role co-operating with MYC to regulate transcription (Bossone et al, 1992), and disrupted MYC-regulated gene expression was a signature of ASXL1-truncated mice (Yang et al, 2018;Zhang et al, 2018); an SP1-like DNA-binding specificity that is similar to that previously observed for the PR-DUB (Dey et al, 2012); and an ability to interact with the nucleosome-remodelling factor subunit BPTF (Jordan-Sciutto et al, 2000).…”