Notch pathway activation targets AML-initiating cell homeostasis and differentiation

Lobry, Camille; Ntziachristos, Panagiotis; Ndiaye‐Lobry, Delphine; Oh, Phil; Cimmino, Luisa; Zhu, Nan; Araldi, Elisa; Hu, Wenhuo; Freund, Jacquelyn; Abdel-Wahab, Omar; Ibrahim, Sherif; Skokos, Dimitris; Armstrong, Scott A.; Levine, Ross L.; Park, Christopher Y.; Aifantis, Iannis

doi:10.1084/jem.20121484

Cited by 137 publications

(145 citation statements)

References 56 publications

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“…Furthermore, NOTCH signaling is required for definitive hematopoiesis and lymphopoiesis, particularly T cell specification, mirroring our findings as KDM2B (a) ectopic expression expanded the T cell compartment and (b) deletion impaired lymphoid development (Figures 2-4). Interestingly, NOTCH functions as a tumor suppressor in myeloid malignancies (60), consistent with our findings that KDM2B restrains KRAS-driven AML. We also found that KDM2B represses WNT signaling through direct transcriptional regulation of several ligands.…”

Section: Methodssupporting

confidence: 90%

Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis

Andricovich¹,

Kai²,

Peng³

et al. 2016

Journal of Clinical Investigation

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Section: Methodssupporting

confidence: 90%

Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis

Andricovich¹,

Kai²,

Peng³

et al. 2016

Journal of Clinical Investigation

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“…Therefore, in both human patients and mouse models, the kinetics of disease development suggests that cooperating mutations are necessary to achieve full malignant transformation. In accordance, cooperation of Tet2 deficiency with KIT activation (Soucie et al 2012;Pastor et al 2013) and with inactivation of the Notch pathway (Lobry et al 2013;Solary et al 2014) was recently demonstrated. However, the mechanistic role of Tet2 loss in this process remains unknown.…”

mentioning

confidence: 57%

Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis

et al. 2015

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DNA methylation is tightly regulated throughout mammalian development, and altered DNA methylation patterns are a general hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in hematological disorders, including acute myeloid leukemia (AML), and has been suggested to protect CG dinucleotide (CpG) islands and promoters from aberrant DNA methylation. In this study, we present a novel Tet2-dependent leukemia mouse model that closely recapitulates gene expression profiles and hallmarks of human AML1-ETO-induced AML. Using this model, we show that the primary effect of Tet2 loss in preleukemic hematopoietic cells is progressive and widespread DNA hypermethylation affecting up to 25% of active enhancer elements. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner but increases relative to population doublings. We confirmed this specific enhancer hypermethylation phenotype in human AML patients with TET2 mutations. Analysis of immediate gene expression changes reveals rapid deregulation of a large number of genes implicated in tumorigenesis, including many down-regulated tumor suppressor genes. Hence, we propose that TET2 prevents leukemic transformation by protecting enhancers from aberrant DNA methylation and that it is the combined silencing of several tumor suppressor genes in TET2 mutated hematopoietic cells that contributes to increased stem cell proliferation and leukemogenesis.

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“…FLT3 is already known as a frequently mutated oncogene in AML, whereas the role of NOTCH2 in this disease is not well understood, although decreased NOTCH2 expression has been linked to AML in 2 reports. 35,36 Cloning and sequencing analysis identified several aberrant splice variants of NOTCH2 and FLT3 that resulted from either skipping of $1 exon or activation of cryptic splicing sites. All these splicing alterations created transcripts that encoded proteins, as demonstrated through expression of NOTCH2-Va, NOTCH2-Vb, FLT3-Va, and FLT3-Vb splice variants in HEK293T cells.…”

Section: Discussionmentioning

confidence: 99%

NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML

Adamia

Bar-Natan

Haibe‐Kains

et al. 2014

Blood

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• Overall, our results suggest that NOTCH2 and FLT3 aberrant splicing is a common event in AML that correlates with disease status and may correlate with disease outcomes. • Selected variants of NOTCH2and FLT3 transcripts were detected in a significant number of AML patients and could be useful as disease markers.Our previous studies revealed an increase in alternative splicing of multiple RNAs in cells from patients with acute myeloid leukemia (AML) compared with CD34 1 bone marrow cells from normal donors. Aberrantly spliced genes included a number of oncogenes, tumor suppressor genes, and genes involved in regulation of apoptosis, cell cycle, and cell differentiation. Among the most commonly mis-spliced genes (>70% of AML patients) were 2, NOTCH2 and FLT3, that encode myeloid cell surface proteins. The splice variants of NOTCH2 and FLT3 resulted from complete or partial exon skipping and utilization of cryptic splice sites. Longitudinal analyses suggested that NOTCH2 and FLT3 aberrant splicing correlated with disease status. Correlation analyses between splice variants of these genes and clinical features of patients showed an association between NOTCH2-Va splice variant and overall survival of patients. Our results suggest that NOTCH2 and FLT3 mis-splicing is a common characteristic of AML and has the potential to generate transcripts encoding proteins with altered function. Thus, splice variants of these genes might provide disease markers and targets for novel therapeutics. (Blood. 2014;123(18):2816-2825

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Notch pathway activation targets AML-initiating cell homeostasis and differentiation

Abstract: Notch behaves as a tumor suppressor in AML, and Notch activation induces cell cycle arrest, differentiation, and apoptosis of AML-initiating cells.

Cited by 137 publications

References 56 publications

Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis

Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis

Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis

NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML

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