Hypermethylation of the Ink4b locus in murine myeloid leukemia and increased susceptibility to leukemia in p15Ink4b-deficient mice

Wolff, Linda; Garin, Matthew T.; Koller, Richard; Bies, Juraj; Liao, Wei; Malumbres, Marcos; Tessarollo, Lino; Powell, Douglas; Perella, Christine M.

doi:10.1038/sj.onc.1207092

Cited by 36 publications

(29 citation statements)

References 30 publications

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“…Although these other mutations involve Ink4a regulators and p16Ink4a itself, it is of note that we observe diminished CNS progenitor proliferation in Zeb1-null mice, and this effect was similar to, or even greater than, that observed with Bmi1 mutation (Molofsky et al, 2005). Interestingly, TGF-␤ and p15Ink4b have key roles in restricting proliferation of T-cell progenitors, and mutation or epigenetic silencing of p15Ink4b leads to lymphoproliferative disease (Latres et al, 2000;Wolff et al, 2003;Lessard and Sauvageau, 2003;Mishra et al, 2005), and is common in leukemia (reviewed by Claus and Lubbert, 2003). It is of note that Zeb1-null mice have a diminished number of T-cell progenitors, which fail to populate the thymus (Higashi et al, 1997;Takagi et al, 1998).…”

Section: Research Articlementioning

confidence: 71%

Zeb1 links epithelial-mesenchymal transition and cellular senescence

et al. 2008

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Overexpression of zinc finger E-box binding homeobox transcription factor 1 (Zeb1) in cancer leads to epithelial-to-mesenchymal transition (EMT) and increased metastasis. As opposed to overexpression, we show that mutation of Zeb1 in mice causes a mesenchymal-epithelial transition in gene expression characterized by ectopic expression of epithelial genes such as E-cadherin and loss of expression of mesenchymal genes such as vimentin. In contrast to rapid proliferation in cancer cells where Zeb1 is overexpressed, this mesenchymal-epithelial transition in mutant mice is associated with diminished proliferation of progenitor cells at sites of developmental defects, including the forming palate, skeleton and CNS. Zeb1 dosage-dependent deregulation of epithelial and mesenchymal genes extends to mouse embryonic fibroblasts (MEFs), and mutant MEFs also display diminished replicative capacity in culture, leading to premature senescence. Replicative senescence in MEFs is classically triggered by products of the Ink4a (Cdkn2a) gene. However, this Ink4a pathway is not activated during senescence of Zeb1 mutant MEFs. Instead, there is ectopic expression of two other cell cycle inhibitory cyclin-dependent kinase inhibitors, p15Ink4b (Cdkn2b) and p21Cdkn1a (Cdkn1a). We demonstrate that this ectopic expression of p15Ink4b extends in vivo to sites of diminished progenitor cell proliferation and developmental defects in Zeb1-null mice.

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Section: Research Articlementioning

confidence: 71%

Zeb1 links epithelial-mesenchymal transition and cellular senescence

et al. 2008

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“…The methylation status of the region 5 0 to the coding sequence of the genes p16, p21, p27, cdk4, cdk6 and JunB was analysed by MSP. MSP primer sequences for p16 were used as reported previously (Wolff et al, 2003). For the genes p21, p27, cdk4, cdk6 and JunB, MSP primer sequences were designed using the online program MethPrimer (Li and Dahiya, 2002) and are available upon request.…”

Section: Preparation Of Primary Cells Infection Of Fetal Liver Cellsmentioning

confidence: 99%

JunB is a gatekeeper for B-lymphoid leukemia

et al. 2007

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Loss of JunB has been observed in human leukemia and lymphoma, but it remains unknown, whether this loss is relevant to disease progression. Here, we investigated the consequences of JunB deficiency using Abelson-induced B-lymphoid leukemia as a model system. Mice deficient in JunB expression succumbed to Abelson-induced leukemia with increased incidence and significantly reduced latency. Similarly, bcr/abl p185-transformed JunB-deficient (junB D/D ) cells induced leukemia in RAG2 À/À mice displaying a more malignant phenotype. These observations indicated that cell intrinsic effects within the junB D/D tumor cells accounted for the accelerated leukemia development. Indeed, explantated bcr/abl p185 transformed junB D/D cells proliferated faster than the control cells. The proliferative advantage emerged slowly after the initial transformation process and was associated with increased expression levels of the cell cycle kinase cdk6 and with decreased levels of the cell cycle inhibitor p16 INK4a . These alterations were due to irreversible reprogramming of the cell, because -once established -accelerated disease induced by junB D/D cells was not reverted by re-introducing JunB. Consistent with this observation, we found that the p16 promoter was methylated. Thus, JunB functions as a gatekeeper during tumor evolution. In its absence, transformed leukemic cells acquire an enhanced proliferative capacity, which presages a more malignant disease.

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“…The high CpG regions of p15 Ink4b promoter and first exon reported to be methylated in certain cancers 20,21 (318-644 bp, GenBank accession no. U66084) was amplified by PCR and cloned in pST-Blue vector (Novagen).…”

Section: Bisulfite Sequencing Analysismentioning

confidence: 99%

KDM2b/JHDM1b, an H3K36me2-specific demethylase, is required for initiation and maintenance of acute myeloid leukemia

Nguyen

Zhang

2011

Blood

189

144

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The histone H3 lysine 36 dimethylspecific demethylase KDM2b/JHDM1b, which is highly expressed in various human leukemias, was previously found to be important in regulating cell proliferation and cellular senescence. However, its functions in leukemia development and maintenance are unclear. Here, we demonstrate that ectopic expression of IntroductionPrevious studies have shown that human leukemic cells from the same patient are composed of heterogeneous cell populations with various proliferation capacities and differentiation status. In the proposed leukemia stem cell (LSC) model, a fraction of LSCs resides at the apex of leukemia cellular hierarchy. Similar to hematopoietic stem cells (HSCs) in normal blood development, LSCs can give rise to the entire cellular hierarchy and sustain leukemia expansion through an unlimited self-renewal capability. 1 This model is supported by studies in which LSC-enriched cell populations, such as the CD34 ϩ CD38 Ϫ leukemic cells in human acute myeloid leukemia (AML), transplanted into SCID mice are able to fully recapitulate the process of leukemia development. 2,3 LSCs can be derived from different cellular compartments according to the leukemia type and disease stage. In a Junb inactivation-induced chronic myeloid leukemia (CML) murine model, the CML-like disease can only develop from Junbinactivated HSCs but not progenitor cells, indicating that LSCs may derive from HSCs. 4 However, in the accelerated and myeloid blast crisis phases of human CML, only leukemic granulocytemacrophage progenitors can be expanded and display an aberrant self-renewing capacity in vitro in the methylcellulose replating assay. 5 In addition, the fact that certain murine AMLs can be induced by retroviral transduction of oncogenes, such as Mll fusion genes, into the granulocyte-macrophage progenitor population indicates that LSCs can originate from committed progenitor cells directly. 6,7 These studies suggest that the "stemness" program of LSCs could be activated by various oncogenic stimuli in different cellular contexts. However, the molecular mechanisms underlying LSC self-renewal is not well understood. 8 The leukemic stem cell model implies that epigenetic regulation at certain critical gene loci might be important in determining the phenotypic difference between self-renewing LSCs and their non-self-renewing progeny. 8 One example that supports this notion comes from the demonstration that the Ink4a-Arf-Ink4b locus, which encodes 3 tumor suppressors, including p16 Ink4a , p15 Ink4b , and p19 Arf is controlled by the Polycomb repressive complex 1 (PRC1) in both normal HSCs and LSCs. 9,10 Biochemical analysis has shown that the PRC1 complex contains an ubiquitin E3 ligase activity and catalyzes the monoubiquitylation of histone H2A at lysine 119, which may serve as an epigenetic mark for the recruitment of other transcriptional repressors to the Ink4a-ArfInk4b locus. 11,12 Consistently, deletion of BMI-1, a component of the PRC1 complex, in LSCs leads to de-repression of Ink4a-Arf expression...

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Hypermethylation of the Ink4b locus in murine myeloid leukemia and increased susceptibility to leukemia in p15Ink4b-deficient mice

Cited by 36 publications

References 30 publications

Zeb1 links epithelial-mesenchymal transition and cellular senescence

Zeb1 links epithelial-mesenchymal transition and cellular senescence

JunB is a gatekeeper for B-lymphoid leukemia

KDM2b/JHDM1b, an H3K36me2-specific demethylase, is required for initiation and maintenance of acute myeloid leukemia

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