scholarly journals Role of KDM2B and Non-Canonical PRC1.1 As a Tumor Suppressor in T-ALL

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2597-2597
Author(s):  
Yusuke Isshiki ◽  
Yaeko Nakajima-Takagi ◽  
Motohiko Oshima ◽  
Kazumasa Aoyama ◽  
Atsunori Saraya ◽  
...  
Keyword(s):  
T Cell ◽  
Sequence Analysis ◽  
Histone Modification ◽  
Target Genes ◽  
Sequence Data ◽  
Lymphoblastic Leukemia ◽  
Peripheral Blood Flow ◽  
Peak Calling ◽  
Chip Sequencing ◽  
T Cell Leukemogenesis

Abstract Introduction: Polycomb repressive complexes (PRCs) play an important role for the transcriptional repression of their target genes through histone modification. KDM2B is a component of non-canonical PRC1.1 and has a role for the recruitment of the complex to the target gene loci. It has a zinc finger-CxxC (ZF-CxxC) domain which specifically binds to unmethylated sequences in CpG islands (CGIs) and deletion of the CxxC domain induces complete loss of KDM2B occupancy and removal of other PRC1.1 components from CGIs. Recent studies revealed that loss of function mutations of several PRC component genes such as EZH2, EED, SUZ12 and BCOR were frequently detected in human T-cell acute lymphoblastic leukemia (T-ALL), which suggested PRCs have a tumor suppressive role in T cell development. Our group have reported conditional knock out of Bcor, encoding a component protein of non-canonical PRC1.1, induced T-ALL in mice. However, it is still unknown how KDM2B and non-canonical PRC1.1 regulate T cell leukemogenesis. Therefore, we performed detailed analysis of mice deficient for Kdm2b ZF-CxxC domain (Kdm2bΔCxxC/ΔCxxC) specifically in hematopoietic cells. Methods: We used the conditional Kdm2b allele (Kdm2bfl) mice, which contains LoxP sites flanking Kdm2b exon 13 encoding the ZF-CxxC domain. To generate hematopoietic cell specific Kdm2b KO mice, we transplanted Kdm2bfl/fl;Cre-ERT total BM cells into lethally irradiated CD45.1+ recipient mice and deleted Kdm2b 4 weeks after transplantation by intraperitoneally injecting of tamoxifen. Results: During the observation period of 300 days, almost all of the Kdm2b KO mice developed lethal T-ALL. They showed thymomegaly and splenomegaly and presented infiltration of donor-derived leukemic cells into the bone marrow, spleen, thymus and peripheral blood. Flow cytometric analysis revealed that T-ALL cells were mainly CD4 and CD8-double positive (DP). Notch1 active mutations in exons 26, 27, 28 or 34 were found in over a half of the T-ALL cases, indicating the Notch1 activation could be a driver for leukemic transformation in this mouse model. RNA sequence analysis of the DP cells revealed activation of Myc, which plays a key role in the development of T-ALL, and their downstream target genes in Kdm2b-deficient T-ALL. ChIP sequence analysis of DP thymocytes expressing 3xFLAG-KDM2B confirmed the binding peaks of KDM2B at the promotor of Myc. Peak calling analysis of the ChIP sequence data revealed that KDM2B was mainly located at transcript start sites (TSS), where KDM2B was co-localized with H2AK119ub1 and H3K27me3 histone marks. In addition, ChIP sequencing of H3K4me3 revealed that the KDM2B target genes include more bivalent genes than non-target genes. We next compared histone modification status around TSS in WT and Kdm2b KO DP cells and Kdm2b-deficient T-ALL cells. Global levels of H2AK119ub1 were significantly decreased in T-ALL cells and the reduction was mainly observed at the promoters of KDM2B target genes. Direct target genes of NOTCH1 including Myc also lost H2AK119ub1 at their promotors in T-ALL cells. Peak calling analysis of KDM2B, BCOR and NOTCH1 ChIP sequence data revealed that their target genes were closely overlapped at the promotor region. Moreover, EZH2 binding peaks were also overlapped with those of KDM2B and NOTCH1, suggesting that non-canonical PRC1.1 and PRC2 cooperatively antagonize NOTCH1-mediated gene activation. KEGG pathway analysis of the genes with overlapping binding peaks among KDM2B, EZH2 and NOTCH1 showed significant enrichment of T cell receptor signaling, Notch1 signaling and cell cycle pathway, all of which play an important role for the development of T-ALL. Of interest, H3K27me3 levels of the common target genes of EZH2, KDM2B, and NOTCH1 were much lower than the EZH2-specific target genes, indicating that H2AK119ub1 plays a key role in the repression of NOTCH1 targets. Conclusions: Our findings suggest that KDM2B recruits non-canonical PRC1.1 at the promotor regions of NOTCH1 targets to restraint thymocytes from transformation in concert with PRC2. Disclosures No relevant conflicts of interest to declare.

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 miR-22-3p Negatively Affects Tumor Progression in T-Cell Acute Lymphoblastic Leukemia

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1726
Author(s):  
Valentina Saccomani ◽  
Angela Grassi ◽  
Erich Piovan ◽  
Deborah Bongiovanni ◽  
Ludovica Di Martino ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Target Genes ◽  
Cell Transformation ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Notch1 Signaling Pathway

T-cell acute lymphoblastic leukemia (T-ALL) is a rare, aggressive disease arising from T-cell precursors. NOTCH1 plays an important role both in T-cell development and leukemia progression, and more than 60% of human T-ALLs harbor mutations in components of the NOTCH1 signaling pathway, leading to deregulated cell growth and contributing to cell transformation. Besides multiple NOTCH1 target genes, microRNAs have also been shown to regulate T-ALL initiation and progression. Using an established mouse model of T-ALL induced by NOTCH1 activation, we identified several microRNAs downstream of NOTCH1 activation. In particular, we found that NOTCH1 inhibition can induce miR-22-3p in NOTCH1-dependent tumors and that this regulation is also conserved in human samples. Importantly, miR-22-3p overexpression in T-ALL cells can inhibit colony formation in vitro and leukemia progression in vivo. In addition, miR-22-3p was found to be downregulated in T-ALL specimens, both T-ALL cell lines and primary samples, relative to immature T-cells. Our results suggest that miR-22-3p is a functionally relevant microRNA in T-ALL whose modulation can be exploited for therapeutic purposes to inhibit T-ALL progression.

Identification of ERG Specific Target Genes by Genome-Wide Screening in T-Lymphoblastic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3788-3788
Author(s):  
Liliana H Mochmann ◽  
Konrad Neumann ◽  
Juliane Bock ◽  
Jutta Ortiz Tanchez ◽  
Arend Bohne ◽  
...  
Keyword(s):  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Specific Treatment ◽  
P Value ◽  
Dna Templates ◽  
Genome Wide ◽  
A Genome ◽  
On Chip ◽  
T Cell Leukemogenesis ◽  
The Impact

Abstract The Ets related gene, ERG, encodes a transcription factor with a vital role in hematopoiesis. Recent findings have shown that ERG knockout mice require a minimum of one functional allele to ensure embryonic blood development and adult stem cell maintenance. Moreover, it was earlier reported that enforced expression of ERG induced oncogenic transformation in 3T3 cells. Overexpression of ERG, observed in a subset of acute T-lymphoblastic and acute myeloid leukemia patients, was associated with an inferior outcome. However, the impact of ERG contributing to this unfavourable phenotype has yet to be determined, as downstream targets of ERG in leukemia remain unknown. Herein, we conducted a genome-wide analysis of ERG target genes in T-lymphoblastic leukemia. Chromatin immunoprecipitation-on-chip array (ChIP-on-chip) analyses were performed using two ERG specific antibodies for the enrichment of ERG-bound DNA templates in T-lymphoblastic leukemia cells (Jurkat) with input DNA or IgG precipitated DNA as controls. Enriched DNA templates and control DNA were differentially labelled and co-hybridized to high resolution promoter chip arrays with 50–75mer probes (770,000) representing 29,000 annotated human transcripts (NimbleGen). Based on two independent ChIP-on-chip assays, bioinformatic analysis (ACME) yielded statistically significant enriched peaks (using a sliding window of 1000 bp, and a P-value < 0.0001) identifying promoter regions of 365 potential ERG target genes. From these genes, clustering by functional annotation was performed using the DAVID database and subsequently genes related to leukemia were further selected for quantitative PCR validation. The design of promoter primers included the highly conserved ETS GGAA DNA binding site. Genes with greater than two-fold enrichment (ERG ChIP versus control) included WNT2 (17-fold), OLIG2 (14-fold), WNT11 (7-fold), CCND1 (5-fold), WNT9A (4-fold), CD7 (3-fold), EPO (3-fold), ERBB4 (3-fold), RPBJL (3-fold), TRADD (3-fold), PIWIL1 (2-fold), TNFRSF25 (2-fold), TWIST1 (2-fold), and HDAC4 (2-fold). Interestingly, enriched target genes involved in developmental processes (WNT2, WNT9A, WNT11, TWIST1, PIWIL1, ERBB4, and OLIG2) have shown oncogenic potential when mutated or overexpressed. Thus, we hypothesize that overexpression of ERG may contribute to T-cell leukemogenesis by the deregulation of these oncogenic targets. Further disclosure of ERG directed downstream pathways may contribute to the design of specific treatment strategies (such as WNT inhibitors) with particular effectiveness in ERG deregulated leukemia.

Notch Signaling Represses Mir-223 in T-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4630-4630
Author(s):  
Samuel D Gusscott ◽  
Florian Kuchenbauer ◽  
Andrew P Weng
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Growth ◽  
Notch Signaling ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Gamma Secretase ◽  
Protein Levels ◽  
Cell Acute Lymphoblastic Leukemia ◽  
T Cell Leukemogenesis

Abstract Abstract 4630 T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of immature T cells that often shows aberrant activation of the Notch1 signaling pathway. Several studies have utilized mRNA expression profiling to identify downstream mediators of oncogenic Notch signaling in this context. Since microRNAs (miRNAs) have in recent years been shown to play important roles in hematological maliganancy, we performed a microarray-based screen for Notch-dependent miRNA expression in T-ALL. Jurkat and P12-Ichikawa cell lines were treated with gamma-secretase inhibitor to block Notch signaling vs. DMSO control for 4 days and profiled using Exigon miRCURY LNA miRNA microarrays. Surprisingly few miRNAs were found to be regulated by this approach; however, one of the hits, miR-223, showed consistent upregulation after gamma-secretase treatment in Jurkat cells and 5 additional human T-ALL cell lines assessed by miRNA qPCR. This observation was unique to human T-ALL as murine models of T-ALL showed no evidence for Notch-dependent miR-223 expression. Given that canonical Notch signaling results in transcriptional activation, our observation that Notch signaling is associated with reduced miR-223 expression suggests an intermediary repressor may be involved. miR-223 has been reported to play an important role in normal granulopoiesis, to be expressed relatively highly in T-ALL with myeloid-like gene features, and most recently to accelerate Notch-mediated T-cell leukemogenesis. To explore potential functional consequences for Notch-dependent miR-223 repression in T-ALL, candidate miR-223 targets identified by TargetScan software were analyzed with Ingenuity Pathway Analysis software, which indicated IGF-1, insulin receptor, PTEN, and ERK5 signaling pathways as the top hits. We recently reported IGF1R signaling to be important for growth and viability of bulk T-ALL cells as well as for leukemia-initiating cell activity. Additionally, we reported that Notch signaling directly upregulates IGF1R transcription by binding to an intronic enhancer which is present between exons 21/22 in the human, but not mouse IGF1R locus. As miR-223 has previously been reported to target IGF1R mRNA and reduce its translation, we hypothesized that Notch signaling may also upregulate net IGF1R protein expression by repressing miR-223. To test this hypothesis, we transduced several human T-ALL cell lines with miR-223 retrovirus and observed a modest decrease in total IGF1R protein levels by western blot; however, no significant change was observed in surface IGF1R levels as assessed by flow cytometry. Addtionally, knockdown of miR-223 by lentiviral expression miR-223 target sequences (miR-223 “sponge”) resulted in modestly increased total IGF1R protein levels, but again showed no demonstrable effect on surface IGF1R levels. Of note, we also observed no apparent effect of either overexpression or knockdown of miR-223 on bulk cell growth or viability. We interpret these findings to suggest that Notch signaling does not have major effects on the miR transcriptome, and that up- or down-modulation of miR-223 in established T-ALL cells does not have significant effects on overall cell growth/viability. Further studies will be required to determine if miR-223 may act in concert with other Notch target genes to modulate cell physiology. Disclosures: No relevant conflicts of interest to declare.

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 &gt;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.

Tal1 and a DNA Binding Mutant (Tal1R188G;R189G) Cooperate with LMO2 To Induce Leukemia in Mice.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1414-1414
Author(s):  
Kyle M. Draheim ◽  
Kimberly Erdkamp ◽  
Eward Arous ◽  
Jennifer A. Calvo ◽  
Michelle A. Kelliher
Keyword(s):  
T Cell ◽  
Dna Binding ◽  
Transgenic Mice ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Ectopic Expression ◽  
Thymocyte Development ◽  
Binding Properties ◽  
Transcriptional Complex ◽  
Dna Binding Properties

Abstract LMO2 is a member of the “LIM only” protein family and required for primitive erythropoiesis and adult vasculogenesis and angiogenesis. In erythroid cells, LMO2 interacts with TAL1 and E47 and LDB1 and GATA-1, thereby forming a transcriptional complex whose target genes include EKLF, CKIT, and p4.2 (protein 4.2). LMO2 was first implicated in leukemogenesis when it was identified in chromosomal translocations t(11;14)(p13;q11) and t(7;11)(q35;p13) found in T cell acute lymphoblastic leukemia (T-ALL) patients. Ectopic expression of LMO2 in mice recapitulates the human disease, albeit at low penetrance and following a long latency. LMO2 has been shown to synergize with TAL1, yet the mechanism of oncogene cooperativity is unknown. Two models have been proposed: the first suggests that LMO2 and TAL1 synergize by forming an active transcriptional complex that induces expression of target genes such as retinaldehyde dehydrogenase 2 (RALDH2) and TALLA1 (a surface marker of T-ALL). The second model proposes that LMO2 and TAL1 sequester the E47/HEB heterodimer, resulting in inhibition of E47/HEB-mediated transcription. To distinguish between these models, we mated our Tal1 transgenic mice and our DNA binding mutant of Tal1(R188G:R189G) with Lmo2 transgenic mice. As expected, transgenic expression of Lmo2 induced disease in 23% of mice after 302 days. Similar to published studies, Tal1 and Lmo2 expression dramatically inhibited thymocyte development and induced T cell leukemia in 100% of the mice with a mean latency of 108 days. To test whether the DNA binding properties of tal1 were required to cooperate with LMO2, we mated mice expressing a DNA binding mutant of Tal1(R188G;R189G) with Lmo2 transgenic mice and found that tumors were induced with similar kinetics; 100% of mice developed disease with an average latency of 107 days. These data suggest LMO2 does not require the DNA-binding properties of Tal1 to induce leukemia in mice and support the model that LMO2 contributes to leukemia through E47/HEB sequestration and inhibition.

Expanding The TLX1-Regulome In T Cell Acute Lymphoblastic Leukemia Towards Long Non-Coding RNAs

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 813-813
Author(s):  
Kaat Durinck ◽  
Joni Van der Meulen ◽  
Maté Ongenaert ◽  
Pieter-Jan Volders ◽  
Annelynn Wallaert ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Protein Coding ◽  
Chip Sequencing ◽  
Lncrna Expression ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Non Coding Rnas

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that results from the malignant transformation of T-cell precursors and affects children, adolescents and adults. In T-ALL, genetic lesions in several possible oncogenes and tumor suppressors have been shown to cooperatively contribute to leukemogenesis. The TLX1 (T-cell leukemia homeobox protein-1, HOX11) oncoprotein is aberrantly expressed in in 5-10% of pediatric patients and 30% of adult T-ALL patients due to chromosomal translocations. Although many downstream protein coding targets genes of TLX1 have been identified, the non-coding network downstream of TLX1 remains elusive. In this study we expand the TLX1 regulome towards long non-coding RNAs (lncRNAs). Hereto we measured the transcriptional response of all protein coding genes and 12,000 lncRNAs following TLX1 knock down in the ALL-SIL cell line using a custom designed mRNA/lncRNA expression platform (Agilent). In addition, similar mRNA-lncRNA expression profiles of 64 primary T-ALL patient samples were generated which included five TLX1+ cases. To establish the direct transcriptional TLX1 targets, we generated TLX1 ChIP-sequencing data from ALL-SIL leukemic cells. We confirm direct regulation of previously established protein coding gene targets and de novo TLX1 motif discovery also identified RUNX1 as an important mediator of the global TLX1 transcriptional network (Della Gatta et al., Nature Medicine, 2012). Complementary to these data, our analysis for the first time establishes the TLX1 driven lncRNAome in thymocyte derived leukemic cells. Remarkably, the majority of TLX1 controlled lncRNAs were upregulated suggesting that they may be implicated in the TLX1 driven repression of protein coding gene expression. Finally, pairwise mRNA-lncRNA correlation analysis allowed functional annotation of TLX1 targeted lncRNAs. In conclusion, we present the first landscaping of the genome-wide binding pattern of TLX1 and provide evidence for a previously unestablished role of lncRNAs in the TLX1 regulatory network. Disclosures: No relevant conflicts of interest to declare.

T-cell acute lymphoblastic leukemia--the associated gene SCL/tal codes for a 42-Kd nuclear phosphoprotein

Blood ◽  
1992 ◽  
Vol 80 (11) ◽  
pp. 2858-2866 ◽  
Author(s):  
AN Goldfarb ◽  
S Goueli ◽  
D Mickelson ◽  
JM Greenberg
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Nuclear Localization ◽  
Dna Sequences ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Bhlh Protein ◽  
Helix Loop Helix ◽  
Cell Acute Lymphoblastic Leukemia

SCL/tal is a putative oncogene originally identified through its involvement in the translocation t(1;14)(p32;q11) present in the leukemic cell line DU.528. Subsequent studies have shown an upstream deletion activating expression of SCL/tal to be one of the most common genetic lesions in T-cell acute lymphoblastic leukemia (T-ALL). The cDNA sequence of SCL/tal encodes a basic helix-loop-helix (bHLH) protein with regions of marked homology to lyl-1 and tal-2, two other bHLH proteins involved in T-ALL chromosomal translocations. The bHLH motif suggests that the SCL/tal product localizes to the nucleus, binds to specific DNA sequences, and regulates transcription of a specific array of target genes. Our studies directly identify the SCL/tal product as a 42-Kd phosphoprotein that efficiently localizes to the nucleus. Deletion mutagenesis has allowed identification of a region critical for nuclear localization, a region that corresponds to the DNA- binding basic domain within the bHLH motif. Because this domain is shared by lyl-1 and tal-2, these latter putative T-cell oncoproteins probably use a nuclear localization mechanism identical to that of SCL/tal.

NOTCH1 pathway activation is an early hallmark of SCL T leukemogenesis

Blood ◽  
2007 ◽  
Vol 110 (10) ◽  
pp. 3753-3762 ◽  
Author(s):  
Joachim R. Göthert ◽  
Rachael L. Brake ◽  
Monique Smeets ◽  
Ulrich Dührsen ◽  
C. Glenn Begley ◽  
...  
Keyword(s):  
T Cell ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Surface Expression ◽  
Normal Surface ◽  
Double Positive ◽  
Functional Link ◽  
Pathway Activation ◽  
Cell Acute Lymphoblastic Leukemia

Abstract The acquired activation of stem cell leukemia (SCL) during T lymphopoiesis is a common event in T-cell acute lymphoblastic leukemia (T-ALL). Here, we generated tamoxifen (TAM)–inducible transgenic mice (lck-ERT2-SCL) to study the consequences of acquired SCL activation during T-cell development. Aberrant activation of SCL in thymocytes resulted in the accumulation of immature CD4+CD8+ (double-positive, DP) cells by preventing normal surface expression of the T-cell receptor αβ (TCRαβ) complex. SCL-induced immature DP cells were further characterized by up-regulated NOTCH1 and generated noncycling polyclonal CD8+TCRβlow cells. The prevalence of these cells was SCL dependent because TAM withdrawal resulted in their disappearance. Furthermore, we observed that SCL activation led to a dramatic up-regulation of NOTCH1 target genes (Hes-1, Deltex1, and CD25) in thymocytes. Strikingly, NOTCH1 target gene up-regulation was already observed after short-term SCL induction, implying that enhanced NOTCH signaling is mediated by SCL and is not dependent on secondary genetic events. These data represent the basis for a novel pathway of SCL-induced leukemogenesis and provide a functional link between SCL and NOTCH1 during this process.

Sign in / Sign up

Export Citation Format

Share Document