Core Transcriptional Regulatory Circuit Controlled by the TAL1 Complex in Human T Cell Acute Lymphoblastic Leukemia

Sanda, Takaomi; Lawton, Lee N.; Barrasa, M. Inmaculada; Fan, Zi Peng; Kohlhammer, Holger; Gutiérrez, Alejandro; Ma, Wenxue; Tatarek, Jessica; Ahn, Yebin; Kelliher, Michelle A.; Jamieson, Catriona; Staudt, Louis M.; Young, Richard A.; Look, A. Thomas

doi:10.1016/j.ccr.2012.06.007

Cited by 292 publications

(412 citation statements)

References 61 publications

(89 reference statements)

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“…Furthermore, replication genes were not occupied by the SCL-LMO2 complex in leukemic T cells (25). Together, these observations indicate a critical role for LMO2 in erythroid cell fate, via the control of DNA replication and the cell cycle that drives Epodependent expansion of erythroid progenitors while impeding their commitment to terminal maturation.…”

Section: Dnmt1mentioning

confidence: 58%

“…LMO2 shares important transcriptional targets with SCL (15,16,25,36). Nonetheless, LMO2 is rarely found at gene promoters (3%) by ChIP sequencing in multipotent progenitors, whereas SCL is more frequently observed within transcriptional start sites (28%) (24), suggesting that LMO2 has SCL-independent functions.…”

Section: Identification Of New Lmo2 Protein-protein Interactions In Hmentioning

confidence: 99%

mentioning

confidence: 99%

“…In particular, in patients who eventually developed T-ALL associated with LMO2 activation after gene therapy, T-cell hyperproliferation was observed early during the preleukemic stage (19). How LMO2 affects erythroid progenitor or T-cell proliferation cannot be inferred from its downstream target genes (12,(24)(25)(26)(27)(28).To understand LMO2 functions, we performed an unbiased screen for LMO2 interaction partners. We show that LMO2 associates with three replication proteins, minichromosome 6 (MCM6), DNA primase (PRIM1), and DNA polymerase delta (POLD1), and that LMO2 influences cell cycle progression and DNA replication in hematopoietic cells, indicating an unexpected function for LMO2.…”

mentioning

confidence: 99%

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The LMO2 oncogene regulates DNA replication in hematopoietic cells

Sincennes

Humbert

Grondin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Oncogenic transcription factors are commonly activated in acute leukemias and subvert normal gene expression networks to reprogram hematopoietic progenitors into preleukemic stem cells, as exemplified by LIM-only 2 (LMO2) in T-cell acute lymphoblastic leukemia (T-ALL). Whether or not these oncoproteins interfere with other DNA-dependent processes is largely unexplored. Here, we show that LMO2 is recruited to DNA replication origins by interaction with three essential replication enzymes: DNA polymerase delta (POLD1), DNA primase (PRIM1), and minichromosome 6 (MCM6). Furthermore, tethering LMO2 to synthetic DNA sequences is sufficient to transform these sequences into origins of replication. We next addressed the importance of LMO2 in erythroid and thymocyte development, two lineages in which cell cycle and differentiation are tightly coordinated. Lowering LMO2 levels in erythroid progenitors delays G1-S progression and arrests erythropoietin-dependent cell growth while favoring terminal differentiation. Conversely, ectopic expression in thymocytes induces DNA replication and drives these cells into cell cycle, causing differentiation blockade. Our results define a novel role for LMO2 in directly promoting DNA synthesis and G1-S progression.M ore than 70% of recurring chromosomal translocations in T-cell acute lymphoblastic leukemia (T-ALL) involve transcription factors that are master regulators of cell fate. These oncogenic transcription factors determine the gene signature and leukemic cell types (1). Whether these DNA-bound factors may have additional roles beyond modulating gene expression remains unknown. LMO2, a 17-kDa protein defined by tandem zinc finger domains, is an essential nucleation factor that assembles a multipartite transcriptional regulatory complex on gene regulatory regions via direct interaction with the TAL1/SCL transcription factor, LDB1, and other DNA binding transcription factors (2-4, reviewed in refs. 5, 6). These complexes drive gene expression programs that determine hematopoietic cell fates at critical branchpoints both during embryonic development (7) and in adult hematopoietic stem cells (8, 9). Lmo2 function is essential in highly proliferative erythroid progenitors (10, reviewed in refs. 5, 6). Interestingly, Lmo2 down-regulation is required for terminal erythroid differentiation (11,12). Because commitment to terminal differentiation is coordinated with growth arrest (13), Lmo2 may have additional molecular functions that impede this critical step marked by growth cessation.In mouse models of T-ALL, LMO1 or LMO2 collaborates with SCL to inhibit the activity of two basic helix-loop-helix (bHLH) transcription factors that control thymocyte differentiation, E2A/ TCF3 and HEB/TCF12, causing differentiation arrest (reviewed in ref. 14). However, this inhibition is not sufficient, per se, for leukemogenesis, because both TAL1 and LYL1 inhibit E proteins but require interaction with LMO1/2 to activate the transcription of a self-renewal gene network in thymocytes (15,16) and to induc...

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Section: Dnmt1mentioning

confidence: 58%

Section: Identification Of New Lmo2 Protein-protein Interactions In Hmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

The LMO2 oncogene regulates DNA replication in hematopoietic cells

Sincennes

Humbert

Grondin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…These involve developmental progression within the mammalian pancreas, the Drosophila heart, and the skeletogenic micromere in the sea urchin embryo (20,21). Well-characterized feedback circuitries have also been identified that stabilize gene expression programs in embryonic stem cells, induced pluripotent stem (iPS) cells, and T-cell acute lymphoblastic leukemia (T-ALL) (22)(23)(24). We suggest that similarly as described for embryonic and cancer stem cells, the positive intergenic feedback circuitry involving EBF1 and FOXO1 acts to reinforce and maintain a pro-B-specific transcription signature.…”

Section: Discussionmentioning

confidence: 99%

Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate

Månsson

Welinder

Åhsberg

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Recent studies have identified a number of transcriptional regulators, including E2A, early B-cell factor 1 (EBF1), FOXO1, and paired box gene 5 (PAX5), that promote early B-cell development. However, how this ensemble of regulators mechanistically promotes B-cell fate remains poorly understood. Here we demonstrate that B-cell development in FOXO1-deficient mice is arrested in the common lymphoid progenitor (CLP) LY6D + cell stage. We demonstrate that this phenotype closely resembles the arrest in B-cell development observed in EBF1-deficient mice. Consistent with these observations, we find that the transcription signatures of FOXO1-and EBF1-deficient LY6D + progenitors are strikingly similar, indicating a common set of target genes. Furthermore, we found that depletion of EBF1 expression in LY6D + CLPs severely affects FOXO1 mRNA abundance, whereas depletion of FOXO1 activity in LY6D + CLPs ablates EBF1 transcript levels. We generated a global regulatory network from EBF1 and FOXO1 genome-wide transcription factor occupancy and transcription signatures derived from EBF1-and FOXO1-deficient CLPs. This analysis reveals that EBF1 and FOXO1 act in a positive feedback circuitry to promote and stabilize specification to the B-cell lineage.

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Super‐Enhancer‐Driven IRF2BP2 is Activated by Master Transcription Factors and Sustains T‐ALL Cell Growth and Survival

Yu,

Zhang,

Chen

et al. 2024

Advanced Science

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Super enhancers (SEs) are large clusters of transcriptional enhancers driving the expression of genes crucial for defining cell identity. In cancer, tumor‐specific SEs activate key oncogenes, leading to tumorigenesis. Identifying SE‐driven oncogenes in tumors and understanding their functional mechanisms is of significant importance. In this study, a previously unreported SE region is identified in T‐cell acute lymphoblastic leukemia (T‐ALL) patient samples and cell lines. This SE activates the expression of interferon regulatory factor 2 binding protein 2 (IRF2BP2) and is regulated by T‐ALL master transcription factors (TFs) such as ETS transcription factor ERG (ERG), E74 like ETS transcription factor 1 (ELF1), and ETS proto‐oncogene 1, transcription factor (ETS1). Hematopoietic system‐specific IRF2BP2 conditional knockout mice is generated and showed that IRF2BP2 has minimal impact on normal T cell development. However, in vitro and in vivo experiments demonstrated that IRF2BP2 is crucial for T‐ALL cell growth and survival. Loss of IRF2BP2 affects the MYC and E2F pathways in T‐ALL cells. Cleavage under targets and tagmentation (CUT&Tag) assays and immunoprecipitation revealed that IRF2BP2 cooperates with the master TFs of T‐ALL cells, targeting the enhancer of the T‐ALL susceptibility gene recombination activating 1 (RAG1) and modulating its expression. These findings provide new insights into the regulatory network within T‐ALL cells, identifying potential new targets for therapeutic intervention.

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Core Transcriptional Regulatory Circuit Controlled by the TAL1 Complex in Human T Cell Acute Lymphoblastic Leukemia

Cited by 292 publications

References 61 publications

The LMO2 oncogene regulates DNA replication in hematopoietic cells

The LMO2 oncogene regulates DNA replication in hematopoietic cells

Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate

Super‐Enhancer‐Driven IRF2BP2 is Activated by Master Transcription Factors and Sustains T‐ALL Cell Growth and Survival

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