scholarly journals KDM2B in polycomb repressive complex 1.1 functions as a tumor suppressor in the initiation of T-cell leukemogenesis

2019 ◽  
Vol 3 (17) ◽  
pp. 2537-2549 ◽  
Author(s):  
Yusuke Isshiki ◽  
Yaeko Nakajima-Takagi ◽  
Motohiko Oshima ◽  
Kazumasa Aoyama ◽  
Mohamed Rizk ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Zinc Finger ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Dependent Manner ◽  
Polycomb Repressive Complex ◽  
Human T Cell ◽  
T Cell Leukemogenesis ◽  
Deficient Mice

Abstract KDM2B together with RING1B, PCGF1, and BCOR or BCORL1 comprise polycomb repressive complex 1.1 (PRC1.1), a noncanonical PRC1 that catalyzes H2AK119ub1. It binds to nonmethylated CpG islands through its zinc finger-CxxC DNA binding domain and recruits the complex to target gene loci. Recent studies identified the loss of function mutations in the PRC1.1 gene, BCOR and BCORL1 in human T-cell acute lymphoblastic leukemia (T-ALL). We previously reported that Bcor insufficiency induces T-ALL in mice, supporting a tumor suppressor role for BCOR. However, the function of BCOR responsible for tumor suppression, either its corepressor function for BCL6 or that as a component of PRC1.1, remains unclear. We herein examined mice specifically lacking the zinc finger-CxxC domain of KDM2B in hematopoietic cells. Similar to Bcor-deficient mice, Kdm2b-deficient mice developed lethal T-ALL mostly in a NOTCH1-dependent manner. A chromatin immunoprecipitation sequence analysis of thymocytes revealed the binding of KDM2B at promoter regions, at which BCOR and EZH2 colocalized. KDM2B target genes markedly overlapped with those of NOTCH1 in human T-ALL cells, suggesting that noncanonical PRC1.1 antagonizes NOTCH1-mediated gene activation. KDM2B target genes were expressed at higher levels than the others and were marked with high levels of H2AK119ub1 and H3K4me3, but low levels of H3K27me3, suggesting that KDM2B target genes are transcriptionally active or primed for activation. These results indicate that PRC1.1 plays a key role in restricting excessive transcriptional activation by active NOTCH1, thereby acting as a tumor suppressor in the initiation of T-cell leukemogenesis.

scholarly journals NKX3.1 is a direct TAL1 target gene that mediates proliferation of TAL1-expressing human T cell acute lymphoblastic leukemia

2010 ◽  
Vol 207 (10) ◽  
pp. 2141-2156 ◽  
Author(s):  
Sophie Kusy ◽  
Bastien Gerby ◽  
Nicolas Goardon ◽  
Nathalie Gault ◽  
Federica Ferri ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Notch Pathway ◽  
Gene Promoter ◽  
Leukemic Cells ◽  
Regulatory Sequence ◽  
Human T Cell ◽  
T Cell Leukemogenesis

TAL1 (also known as SCL) is expressed in >40% of human T cell acute lymphoblastic leukemias (T-ALLs). TAL1 encodes a basic helix-loop-helix transcription factor that can interfere with the transcriptional activity of E2A and HEB during T cell leukemogenesis; however, the oncogenic pathways directly activated by TAL1 are not characterized. In this study, we show that, in human TAL1–expressing T-ALL cell lines, TAL1 directly activates NKX3.1, a tumor suppressor gene required for prostate stem cell maintenance. In human T-ALL cell lines, NKX3.1 gene activation is mediated by a TAL1–LMO–Ldb1 complex that is recruited by GATA-3 bound to an NKX3.1 gene promoter regulatory sequence. TAL1-induced NKX3.1 activation is associated with suppression of HP1-α (heterochromatin protein 1 α) binding and opening of chromatin on the NKX3.1 gene promoter. NKX3.1 is necessary for T-ALL proliferation, can partially restore proliferation in TAL1 knockdown cells, and directly regulates miR-17-92. In primary human TAL1-expressing leukemic cells, the NKX3.1 gene is expressed independently of the Notch pathway, and its inactivation impairs proliferation. Finally, TAL1 or NKX3.1 knockdown abrogates the ability of human T-ALL cells to efficiently induce leukemia development in mice. These results suggest that tumor suppressor or oncogenic activity of NKX3.1 depends on tissue expression.

KLF4 Acts As a Tumor Suppressor in T-Acute Lymphoblastic Leukemia and Negatively Regulates Human T Cell Development and Homeostasis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2405-2405
Author(s):  
Bing Xu ◽  
Peng Li
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Cell Development ◽  
Dependent Manner ◽  
Human T Cell

Abstract The transcription factor Kruppel-like factor 4 (KLF4) may induce tumorigenesis or suppress tumor growth in a tissue-dependent manner. We found that overexpression of KLF4 induced not only human acute T-acute lymphoblastic leukemia (T-ALL) cell lines but also primary samples from T-ALL patients to undergo apoptosis through the BCL2/BCLXL pathway in vitro. T cell-associated genes including BCL11B, GATA3, and TCF7 were negatively regulated by KLF4 overexpression. Especially, KLF4 induced SUMOylation and degradation of BCL11B. However, the KLF4-induced apoptosis in T-ALL was rescued by the in vivo microenvironment. Furthermore, the invasion capacity of T-ALL to hosts was compromised when KLF4 was overexpressed. In normal human T cells, the overexpression of KLF4 severely impaired T cell development at early stages, but the blockage of T cell development was resumed by restoration of GATA3 or ICN1. In summary, our data demonstrate that KLF4 acts as a tumor suppressor in malignant T cells and that downregulation of KLF4 may be a prerequisite for early human T cell development and homeostasis. Disclosures No relevant conflicts of interest to declare.

Notch1 Provides a Proliferative Signal in Mouse T Cell Leukemia by Directly Targeting c-Myc.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1434-1434
Author(s):  
Kyle M. Draheim ◽  
Vishva M. Sharma ◽  
Jennifer A. Calvo ◽  
Leslie A. Cunningham ◽  
Nicole Hermance ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Target Gene ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Dependent Manner ◽  
Genetic Event ◽  
Leukemic Cell Lines ◽  
Human T Cell

Abstract As demonstrated in mouse models and in primary human T cell leukemic samples, gain of function mutation(s) in Notch1 is a common genetic event in T cell acute lymphoblastic leukemia (T-ALL). The Notch1 receptor signals through a γ-secretase-dependent process that releases intracellular Notch1 from the membrane to the nucleus where it forms part of a transcriptional activator complex. We have demonstrated that mouse leukemic growth is Notch1-dependent, since treatment with γ-secretase inhibitors (GSI) results in rapid cell cycle arrest and/or apoptosis. To specifically identify Notch1 target gene(s) in leukemia, we developed mouse T cell leukemic cell lines that express intracellular Notch1 in a doxycycline-dependent manner. Using gene expression profiling and chromatin immunoprecipitation, we identified c-myc as a novel and direct Notch1 target gene. Consistent with these findings, retroviral insertional mutagenesis screening of our tal1 leukemic mouse model reveal common insertions in either notch1 or c-myc. Retroviral expression of c-myc, like intracellular Notch1, rescues the growth arrest and apoptosis associated with GSI treatment or Notch1 inhibition in 83% mouse tal1 leukemic cell lines tested. Yet in a subset of leukemic cell lines, retroviral expression of c-myc fails to rescue leukemic growth, whereas expression of intracellular Notch1 in these lines remains capable of restoring growth. These data suggest that additional Notch1 target genes other than c-myc contribute to leukemogenesis. Other Notch1 target genes in thymocyte developement and their potential role in leukemogenesis will be discussed.

Immunotoxin studies in a model of human T-cell acute lymphoblastic leukemia developed in severe combined immune-deficient mice

1994 ◽  
Vol 24-25 (1-3) ◽  
pp. 315-329 ◽  
Author(s):  
B. J. Morland ◽  
D. Boehm ◽  
S. U. Flavell ◽  
J. A. Kohler ◽  
D. J. Flavell
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Human T Cell ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Deficient Mice

Genome-Wide Analysis Reveals Conserved and Divergent Features of Notch1/RBPJ Binding in Human and Murine T Lymphoblastic Leukemia Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5236-5236
Author(s):  
Jon C Aster ◽  
Hongfang Wang ◽  
James Zou ◽  
Yumi Yashiro-Ohtani ◽  
Bo Zhao ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Cell Lines ◽  
Binding Sites ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Human T Cell ◽  
Two Factors

Abstract Abstract 5236 Activated Notch1 regulates gene expression by associating with the DNA-binding factor RBPJ and is an important oncoprotein in murine and human T cell acute lymphoblastic leukemia/lymphoma (T-ALL), yet the interplay between Notch1 and other factors that regulate the transcriptional output of T-ALL cells is poorly understood. Using ChIP-Seq and starting with Notch1-dependent human and murine T-ALL cell lines, we find that Notch1 binds preferentially to promoters, to RBPJ binding sites, and near sites for ZNF143, as well as Ets and Runx factors. By ChIP-Seq, ZNF143 binds to ∼40% of Notch1 sites, whereas Ets1 binding is observed within 100 basepairs of ∼70% of genomic Notch1 binding sites. Notch1/ZNF143 “co-sites” have high Notch1 and ZNF143 signals, frequent co-binding of RBPJ to sites embedded within ZNF143 motifs, strong promoter bias, and low mean levels of “activated” chromatin marks. RBPJ and ZNF143 binding to DNA is mutually exclusive in vitro, suggesting RBPJ/Notch1 and ZNF143 complexes exchange on these sites in T-ALL cell lines. In contrast, Ets1 binding sites flank RBPJ/Notch1 binding sites and are associated with high levels of activated chromatin marks, whereas Runx sites are predominantly intergenic. Although Notch1 predominantly binds promoters, ∼75% of direct Notch1 target genes lack promoter binding and appear to be regulated by enhancers, which were identified near MYC, DTX1, IGF1R, IL7R and the GIMAP gene cluster. Both Ets1 and Notch1 binding to an intronic enhancer located in DTX1 were required for expression of this well characterized Notch1 target gene, suggesting that these two factors coordinately regulate DTX1 expression. Although the association of Notch1 binding with ZNF143, Ets, and Runx sites was highly conserved, binding near certain important genes showed substantial divergence. For example, in human T-ALL lines Notch1/RBPJ bind a 3' enhancer near the IL7R gene, whereas in murine T-ALL lines no binding was observed near Il7r. Similarly, in human T-ALL lines Notch1/RBPJ bound an enhancer located ∼565 kb 5' of MYC, whereas in murine T-ALL cells Notch1/RBPJ bound an enhancer located ∼1 Mb 3' of Myc. Human and murine T-ALL genomes also have many sites that bind only RBPJ. Murine RBPJ “only” sites are highly enriched for imputed sites for the corepressor REST, whereas human RPBJ “only” sites lack REST motifs and are more highly enriched for imputed CREB binding sites. Thus, there is a conserved network of cis-regulatory factors that interacts with Notch1 to regulate gene expression in T-ALL cell lines, as well as novel classes of divergent RBPJ “only” sites that also likely regulate transcription. To extend these findings to normal and pathophysiologic tissues, ChIP-Seq was used to identify RBPJ/Notch1 binding sites in primary murine thymocytes and primary murine T-ALL associated with Notch1 gain-of-function mutations. Early findings appear to indicate that primary T-ALLs closely resemble normal DN3a thymocytes in terms of the distribution of Notch1 binding sites and associated chromatin marks. These data suggest that Notch1-driven T-ALLs epigenetically resemble the DN3a stage of T cell development, during which Notch1 signaling is high and cells are rapidly proliferating. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia

2013 ◽  
Vol 210 (8) ◽  
pp. 1545-1557 ◽  
Author(s):  
Marc R. Mansour ◽  
Takaomi Sanda ◽  
Lee N. Lawton ◽  
Xiaoyu Li ◽  
Taras Kreslavsky ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Lymphoblastic Leukemia ◽  
Optimal Growth ◽  
Down Regulation ◽  
Protein Levels ◽  
Mirna Genes ◽  
Human T Cell ◽  
Cell Acute Lymphoblastic Leukemia

The oncogenic transcription factor TAL1/SCL is aberrantly expressed in 60% of cases of human T cell acute lymphoblastic leukemia (T-ALL) and initiates T-ALL in mouse models. By performing global microRNA (miRNA) expression profiling after depletion of TAL1, together with genome-wide analysis of TAL1 occupancy by chromatin immunoprecipitation coupled to massively parallel DNA sequencing, we identified the miRNA genes directly controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. The most dynamically regulated miRNA was miR-223, which is bound at its promoter and up-regulated by the TAL1 complex. miR-223 expression mirrors TAL1 levels during thymic development, with high expression in early thymocytes and marked down-regulation after the double-negative-2 stage of maturation. We demonstrate that aberrant miR-223 up-regulation by TAL1 is important for optimal growth of TAL1-positive T-ALL cells and that sustained expression of miR-223 partially rescues T-ALL cells after TAL1 knockdown. Overexpression of miR-223 also leads to marked down-regulation of FBXW7 protein expression, whereas knockdown of TAL1 leads to up-regulation of FBXW7 protein levels, with a marked reduction of its substrates MYC, MYB, NOTCH1, and CYCLIN E. We conclude that TAL1-mediated up-regulation of miR-223 promotes the malignant phenotype in T-ALL through repression of the FBXW7 tumor suppressor.

scholarly journals An Oncogene-Regulated Epigenetic Switch in T Cell Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 56-56
Author(s):  
Panagiotis Ntziachristos ◽  
Aristotelis Tsirigos ◽  
Grant Welstead ◽  
Thomas Trimarchi ◽  
Linda Holmfeldt ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Lymphoblastic Leukemia ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cure Rate ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2 ◽  
Histone 3

Abstract Although the cure rate for acute lymphoblastic leukemia (ALL), a frequent pediatric leukemia, has improved dramatically, the overall prognosis remains dismal due to frequent disease relapse and the absence of non-cytotoxic targeted therapy options. Up to 25% of children fail frontline therapy and in these cases prognosis is dismal and the cure rate is approximate 20%. Main current therapies are based on intensive induction chemotherapy that is most frequently coupled to intrathecal chemotherapy alone or with cranial irradiation for central nervous system prophylaxis, which has severe short and long-term side effects. Thus, the ultimate and most critical aim for developing new treatments in different types of leukemia is to block the effects of specific cancer-inducing oncogenes. Others and we have previously shown that T cell ALL (T-ALL) is characterized by activating mutations in the NOTCH signaling pathway. It is currently unclear how key transcription factors in T-ALL such as NOTCH1 recruit the epigenetic machinery and bring together different chromosomal domain, in order to carry out the oncogenic transformation program. We generated evidence that NOTCH1 oncogenic action leads to important epigenetic changes through antagonizing the polycomb repressive complex 2 (PRC2) and leads to loss of the repressive mark histone 3 lysine 27 di/tri-methylation (H3K27me2/3). Moreover, we identified inactivating mutations of the polycomb repressive complex 2 (PRC2), the “writer” of Histone 3 lysine 27 methylation, in primary samples from human patients revealing a tumor suppressor role for the complex in T-ALL. Further extending our work on the H3K27me3 mark, we showed the oncogenic role for the Jumonji d3 (JMJD3) demethylase. Functionally, genomic ablation of the JMJD3 modulator as well as targeting with a specific chemical inhibitor, GSKJ4, generated by GlaxoSmithKline, leads to apoptosis and cell cycle arrest of T-ALL lines and primary cells. Genetic ablation of JMJD3 leads to slower initiation of the disease with significantly improved survival rates of the mice. Surprisingly, UTX acts as a tumor suppressor in the context of the same disease, as part of different transcriptional complexes, and we found that it is genetically inactivated in T-ALL patients. In light of recent developments on novel epigenetic inhibitors against JMJD3, these findings pave the way to specific pharmacological targeting of T cell leukemia. Based on this activity of Notch1 oncogene on epigenetic marks we further hypothesized that the switch from physiological to oncogenic activity might be mediated by changes in enhancer-promoter interaction networks forming chromosomal domains. A substantial percentage of these interactions are likely to be specific for the malignant state, and their disruption with epigenetic pharmacological inhibitors would not potentially affect healthy tissues. Studies in our laboratory show for the first time in leukemia that NOTCH1 chromatin binding sites are associated with enhancer-promoter interactions at oncogenic loci, using up-to-date chromosome conformation capture technology. We hereby show the importance of these interactions for oncogenic gene expression and pharmacological targeting of leukemic cells. These findings lend further rationale to the use of epigenetic drugs for targeted treatment of T cell leukemia. Disclosures Kruidenier: GlaxoSmithKline: Employment. Prinjha:GlaxoSmithKline: Employment.

RUNX1 promotes cell growth in human T-cell acute lymphoblastic leukemia by transcriptional regulation of key target genes

2018 ◽  
Vol 64 ◽  
pp. 84-96 ◽  
Author(s):  
Catherine E. Jenkins ◽  
Samuel Gusscott ◽  
Rachel J. Wong ◽  
Olena O. Shevchuk ◽  
Gurneet Rana ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Growth ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Human T Cell ◽  
Cell Acute Lymphoblastic Leukemia

LEF1 Is a Tumor Suppressor in T Cell Acute Lymphoblastic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3802-3802
Author(s):  
Alejandro Gutierrez ◽  
Takaomi Sanda ◽  
Stuart Winter ◽  
Richard S. Larson ◽  
Lewis B. Silverman ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Suppressor Activity ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Expression Microarrays

Abstract In an effort to further unravel the molecular pathogenesis of T cell acute lymphoblastic leukemia (T-ALL), we performed array CGH on diagnostic specimens from 47 pediatric patients with T-ALL. The LEF1 transcription factor is best known as a positive mediator of oncogenic β-catenin signaling, and it is required for the expression of MYC, Cyclin D1 and Survivin in some contexts, including some normal hematopoietic progenitors. Additionally, Lef1 has been shown to be required for the survival of murine Notch-dependent T cell lymphoma cells. We were thus surprised to find highly focal deletions of LEF1 in 10.6 % (n = 5 of 47) of primary T-ALL patient samples, with 3 cases harboring homozygous deletions and 2 harboring heterozygous deletions of this locus. These deletions involved no other known genes. We then sequenced this gene in 45 of these cases and found heterozygous mutations in 3 additional T-ALL samples, including 2 cases with frameshift mutations predicted to truncate the protein prior to its context-dependent activation and HMG box domains, and one case with an Asp85Asn substitution. Seven of the eight samples harboring LEF1 abnormalities also had mutations in the heterodimerization or PEST domains of NOTCH1. In an effort to characterize the biologic consequences of LEF1 loss in T-ALL, we took advantage of expression microarrays that were previously performed on most of these samples. LEF1 loss defines a novel T-ALL subtype characterized by arrest at the CD1-positive early cortical stage, and whose gene expression profile resembles that of HOX11-positive cases, although expression of HOX11 was generally low in these samples. Loss of LEF1 was mutually exclusive to overexpression of TAL1 and of the HOXA/MEIS1 cluster. Interestingly, LEF1-negative T-ALL cases were associated with increased expression of MYC, and gene set enrichment analysis identified a significant association between LEF1 loss and upregulation of MYC target genes. In addition to its role as a transcriptional activator in the setting of active WNT/β-catenin signaling, LEF1 can also act as a transcriptional repressor in some cellular contexts. Experiments are currently underway to establish the mechanism mediating the tumor suppressor activity of LEF1 in T-ALL.

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