Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation

Nagase, Reina; Inoue, Daichi; Pastore, Alessandro; Fujino, Takeshi; Hou, Hsin‐An; Yamasaki, Norimasa; Goyama, Susumu; Saika, Makoto; Kanai, Akinori; Sera, Yasuyuki; Horikawa, Sayuri; Ota, Yasunori; Asada, Shuhei; Hayashi, Yasutaka; Kawabata, Kimihito C.; Takeda, Reina; Tien, Hwei‐Fang; Honda, Hiroaki; Abdel‐Wahab, Omar; Kitamura, Toshio

doi:10.1084/jem.20171151

Cited by 129 publications

(137 citation statements)

References 66 publications

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“…ASXL1 mutations occur in various types of myeloid malignancies, most commonly are frameshift or nonsense variants, and have been associated with poor prognosis in AML, MDS, and CMML . Functional studies in mice showed that Asxl1 haploinsufficiency leads to the development of MDS‐like disease, and expression of a truncated Asxl1 protein induces altered function of HSC and increased susceptibility to leukemic transformation …”

Section: Functional Implications Of Recurrent Gene Mutations In Chmentioning

confidence: 99%

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Clonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications

Hartmann

Metzeler

2019

Genes Chromosomes & Cancer

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Myeloid neoplasms including myelodysplastic syndromes and acute myeloid leukemia (AML) originate from hematopoietic stem cells through sequential acquisition of genetic and epigenetic alterations that ultimately cause the disease‐specific phenotype of impaired differentiation and increased proliferation. It has become clear that preleukemic clonal hematopoiesis (CH), characterized by an expansion of stem and progenitor cells that carry somatic mutations but are still capable of normal differentiation, can precede the development of clinically overt myeloid neoplasia by many years. CH commonly develops in the aging hematopoietic system, yet progression to myelodysplasia or AML is rare. The discovery that myeloid neoplasms frequently develop from premalignant precursor conditions that are detectable in many healthy individuals has important consequences for the diagnosis, and potentially for the treatment of these disorders. In this review, we summarize the current knowledge on CH as a precursor of myeloid cancers and the implications of CH‐related gene mutations in the diagnostic workup of patients with suspected myelodysplastic syndrome. We will discuss the risk of progression associated with CH in healthy persons and in patients undergoing chemotherapy for a non‐hematologic cancer, and the significance of CH in autologous and allogeneic stem cell transplantation. Finally, we will review the significance of preleukemic clones in AML and their persistence in patients who achieve a remission after chemotherapeutic treatment.

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Section: Functional Implications Of Recurrent Gene Mutations In Chmentioning

confidence: 99%

“…59 Functional studies in mice showed that Asxl1 haploinsufficiency leads to the development of MDS-like disease, and expression of a truncated Asxl1 protein induces altered function of HSC and increased susceptibility to leukemic transformation. [60][61][62]…”

Section: Functional Implications Of Recurrent Gene Mutations In Chmentioning

confidence: 99%

Clonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications

Hartmann

Metzeler

2019

Genes Chromosomes & Cancer

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“…We and others have shown that Asxl1 mutations can result in loss of function and lead to MDS-like disease in mice (14,15). Studies from several groups have also shown that truncated mutations of Asxl1 generated gain of function and dominant-negative function, leading to myeloid leukemia (52)(53)(54). Future work to investigate the hematopoietic phenotypes in truncated Asxl1 and haploinsufficient Nf1-mutant mice is warranted.…”

Section: Discussionmentioning

confidence: 94%

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

Zhang¹,

He²,

Bai³

et al. 2018

Journal of Clinical Investigation

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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.

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“…Using a conditional knock‐in approach, Nagase et al showed that expression of the AML‐associated ASXL1 mutant led to global reductions of H3K4me3 and H2AK119ub. H3K27me3 levels were reduced specifically at HoxA loci, despite minimal changes in global H3K27me3 (Nagase et al , ). In line with the observed reduction in H2AK119ub, Asada et al .…”

Section: Epigenetic Dysregulation In Paediatric Amlmentioning

confidence: 99%

Epigenetics of paediatric acute myeloid leukaemia

2019

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Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation

Abstract: Nagase and Inoue et al. generated a novel Asxl1 mutant mouse model to mimic clonal hematopoiesis and myelodysplastic syndromes caused by ASXL1 mutations and elucidated the effects of mutant versus wild-type ASXL1 on hematopoiesis, gene expression, and chromatin state.

Cited by 129 publications

References 66 publications

Clonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications

Clonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications

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

Epigenetics of paediatric acute myeloid leukaemia

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