Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo

Abdel-Wahab, Omar; Gao, Jie; Adli, Mazhar; Dey, Anwesha; Trimarchi, Thomas; Chung, Young Rock; Kuscu, Cem; Hricik, Todd; Ndiaye‐Lobry, Delphine; LaFave, Lindsay M.; Koche, Richard P.; Shih, Alan H.; Guryanova, Olga A.; Kim, Eunhee; Li, Sheng; Pandey, Suveg; Shin, Joseph; Telis, Leon; Liu, Jinfeng; Bhatt, Parva; Monette, Sébastien; Zhao, Xinyang; Mason, Christopher E.; Park, Christopher Y.; Bernstein, B; Aifantis, Iannis; Levine, Ross L.

doi:10.1084/jem.20131141

Cited by 295 publications

(223 citation statements)

References 54 publications

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“…Ezh2 D/D mice showed a significant leukopenia, in part due to impaired lymphopoiesis as previously reported 31,32 enhanced apoptosis especially in LSK cells (Fig. 2d) 25,36 . Consistent with these findings, we found that Rx291/Ezh2 D/D LSK cells generated significantly fewer colonies in vitro than WT and Rx291 LSK cells ( (Table 1).…”

Section: Resultssupporting

confidence: 84%

Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation

et al. 2014

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Loss-of-function mutations of EZH2, a catalytic component of polycomb repressive complex 2 (PRC2), are observed in B10% of patients with myelodysplastic syndrome (MDS), but are rare in acute myeloid leukaemia (AML). Recent studies have shown that EZH2 mutations are often associated with RUNX1 mutations in MDS patients, although its pathological function remains to be addressed. Here we establish an MDS mouse model by transducing a RUNX1S291fs mutant into hematopoietic stem cells and subsequently deleting Ezh2. Ezh2 loss significantly promotes RUNX1S291fs-induced MDS. Despite their compromised proliferative capacity of RUNX1S291fs/Ezh2-null MDS cells, MDS bone marrow impairs normal hematopoietic cells via selectively activating inflammatory cytokine responses, thereby allowing propagation of MDS clones. In contrast, loss of Ezh2 prevents the transformation of AML via PRC1-mediated repression of Hoxa9. These findings provide a comprehensive picture of how Ezh2 loss collaborates with RUNX1 mutants in the pathogenesis of MDS in both cell autonomous and non-autonomous manners.

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Section: Resultssupporting

confidence: 84%

Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation

et al. 2014

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“…We primarily focused on 654 genes that are known to be involved in regulating hematopoietic cell development and/or to promote leukemogenesis, based on previously published studies (Abdel-Wahab et al, 2013; Chambers et al, 2007; Shlush et al, 2014). By overlapping with the DhMRs or DMRs identified above, we observed a significant number of these genes with altered 5hmC or 5mC modifications (Figures 6D and S6C–E).…”

Section: Resultsmentioning

confidence: 99%

Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice

et al. 2015

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Summary TET1/2/3 are methylcytosine dioxygenases that regulate cytosine hydroxymethylation. Tet1/2 are abundantly expressed in HSC/HPCs and are implicated in hematological malignancies. Tet2-deletion in mice causes myeloid malignancies, while Tet1-null mice develop B-cell lymphoma after an extended period of latency. Interestingly, TET1/2 are often concomitantly downregulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/2 in HSC maintenance and development of hematological malignancies using Tet1/2 double knockout (DKO) mice. DKO and Tet2−/− HSC/HPCs showed overlapping and unique 5hmC and 5mC profiles, and behaved differently. DKO mice exhibited strikingly decreased incidence and delayed-onset of myeloid malignancies compared to Tet2−/− mice, and in contrast developed lethal B-cell malignancies. Transcriptome analysis of DKO tumors revealed expression changes in many genes dysregulated in human B-cell malignancies, such as LMO2, BCL6 and MYC. These results highlight the critical roles of TET1/2 individually and together via communication in the pathogenesis of hematological malignancies.

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“…49,89,90 Knockdown of Asxl1 in mouse results in impaired lymphoid and myeloid differentiation and multi-lineage cytopenias. 91 Collectively, these results suggest that both germline and somatic mutations in ASXL1 cause lower blood cell counts. The transcription factor ETS2 has been shown to regulate phenotypic switch from erythroid to megakaryocyte in acute megakaryocytic leukemia (AMKL), and overexpression of ETS2 results in altered sensitivity to chemotherapy drugs.…”

Section: Relationship Of Wbc Loci To Hematologic Disease and Therapymentioning

confidence: 92%

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

Tajuddin

Schick

Eicher

et al. 2016

The American Journal of Human Genetics

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White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

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Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo

Abstract: Loss of Asxl1 results in myelodysplastic syndrome, whereas concomitant deletion of Tet2 restores HSC self-renewal and triggers a more severe disease phenotype distinct from that seen in single-gene knockout mice.

Cited by 295 publications

References 54 publications

Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation

Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation

Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

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