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SCL and LMO1 reprogram thymocytes into self-renewing cells.

ABSTRACT: The SCL and LMO1 oncogenic transcription factors reprogram thymocytes into self-renewing pre-leukemic stem cells (pre-LSCs). Here we report that SCL directly interacts with LMO1 to activate the transcription of a self-renewal program coordinated by LYL1.

ORGANISM(S): Mus musculus

PROVIDER: GSE74659 | GEO | 2015/11/05

SECONDARY ACCESSION(S): PRJNA301090

REPOSITORIES: GEO

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SCL and LMO1 reprogram thymocytes into self-renewing cells.

Project description:The SCL and LMO1 oncogenic transcription factors reprogram thymocytes into self-renewing pre-leukemic stem cells (pre-LSCs). Here we report that SCL directly interacts with LMO1 to activate the transcription of a self-renewal program coordinated by LYL1. Gene expression profiles of thymocytes from SCL-LMO1 transgenic and age-matched non transgenic Cd3Îµ-/- mice were compared to identify candidate genes that confer self-renewal capability to pre-leukemic thymocytes.

2015-11-05 | E-GEOD-74659 | biostudies-arrayexpress

SCL, LMO1 and Notch1 reprogram thymocytes into self-renewing cells.

Project description: Not available

| S-EPMC4270438 | biostudies-literature

Progression from the preleukemic stage to acute leukemia in TAL1/SCL-LMO1 transgenic mice

Project description:The TAL1/SCL and LMO1 oncogenic transcription factors establish a pre-leukemic state by reprogramming thymocytes into self-renewing pre-leukemic stem cells (pre-LSCs). Pre-TCR signaling accelerates the progression to T-cell acute lymphoblastic leukemia (T-ALL). To directly address the importance of pre-TCR signaling in driving progression to T-ALL, we leverage on Cd3-deficient mice in which pre-TCR signaling and progression through β-selection is abrogated. In the absence of pre-TCR signaling in Cd3ε-deficient SCL-LMO1 transgenic mice, T-ALL onset is delayed by 150 days. Despite the absence of pre-TCR/CD3 signaling in these mice, we show that leukemic thymocytes exhibit the gene expression profiles of thymocytes that have undergone β-selection, i.e. exhibiting a re-activation of pre-TCR-driven proliferation signature, and a down regulation of HEB/TCF12 target genes. Lastly, monoallelic deletion of Heb is sufficient to accelerate T-ALL onset in Cd3ε-deficient SCL-LMO1 transgenic mice. Together, these results underscore the role of HEB/TCF12 as a tumor suppressor in T-ALL.

2022-03-27 | GSE198506 | GEO

Shared roles for Scl and Lyl1 in murine platelet production and function

Project description:The Stem Cell Leukemia (Scl or Tal1) protein forms part of a multimeric transcription factor complex required for normal megakaryopoiesis. However, unlike other members of this complex such as Gata1, Fli1 and Runx1, mutations of Scl have not been observed as a cause of inherited thrombocytopenia. We postulated that functional redundancy with its closely related family member, Lymphoblastic Leukemia 1 (Lyl1) might explain this observation. To determine if Lyl1 can substitute for Scl in megakaryopoiesis, we examined the platelet phenotype of mice lacking one or both factors in megakaryocytes. Conditional Scl knockout mice crossed with transgenic mice expressing Cre recombinase under the control of the mouse platelet factor 4 (Pf4) promoter generated megakaryocytes with markedly reduced but not absent Scl. These Pf4SclcKO mice had mild thrombocytopenia and subtle defects in platelet aggregation. However, Pf4SclcKO mice generated on a Lyl1-null background (double knockout, DKO mice) had severe macrothrombocytopenia, abnormal megakaryocyte morphology, defective pro-platelet formation and markedly impaired platelet aggregation. DKO megakaryocytes, but not single knockouts, had reduced expression of Gata1, Fli1, Nfe2 and many other genes that cause inherited thrombocytopenia. These gene expression changes were significantly associated with shared Scl and Lyl1 E-box binding sites that were also enriched for Gata1, Ets and Runx1 motifs. Thus, Scl and Lyl1 share functional roles in platelet production and function by regulating expression of partner proteins including Gata1 and Fli1. We propose that this functional redundancy provides one explanation for the absence of Scl and Lyl1 mutations as a cause of inherited thrombocytopenia.

2020-12-21 | GSE125025 | GEO

Progression from the preleukemic stage to acute leukemia in TAL1/SCL-LMO1 transgenic mice

Project description:Progression from the preleukemic stage to acute leukemia in TAL1/SCL-LMO1 transgenic mice

| PRJNA815658 | ENA

LMO1 Synergizes with MYCN to Promotes Neuroblastoma Initiation and Metastasis

Project description:High levels of LMO1 expression synergizes with MYCN to accelerate neuroblastomagenesis, enhance disease penetrance and promote widespread metastasis in zebrafish. Transcriptomic analysis of human neuroblasotma cells with programed expression of LMO1 vs vector control or neuroblastoma cells with differential endogenous LMO1 expression revealed that gene signitures affecting tumor cell-extracellular matrix interaction are significantly associated with high levels of LMO1 expression. Our findings provide compelling evidence for a major pathogenic role of LMO1 in MYCN-driven neuroblastoma.

2017-07-31 | GSE90087 | GEO

A novel role for Lyl1 in primitive erythropoiesis

Project description:Stem Cell Leukemia (Scl or Tal1) and Lymphoblastic Leukemia 1 (Lyl1) are highly related members of the basic helix-loop-helix (bHLH) family of transcription factors that are co- expressed in hematopoietic stem cells and the erythro-megakaryocytic lineages. Previous studies suggest that Scl is essential for hematopoietic development including primitive erythropoiesis. However, analysis of single-cell RNA-sequencing data of early embryos showed that primitive erythroid cells express both Scl and Lyl1. Therefore, to determine whether Lyl1 has a functional role in erythropoiesis, we crossed conditional Scl mice with transgenic mice expressing a Cre recombinase under the control of the Epo receptor, active in erythroid progenitors. Surprisingly, embryos with markedly reduced expression of Scl from E9.5 survived to adulthood. In contrast, mice with reduced expression of Scl and absence of Lyl1 (double knockout; DKO) died at E10.5 due to progressive loss of erythropoiesis. Consistent with a phenocopy of Gata1-null mice, gene expression profiling of DKO yolk sacs prior to the loss of erythrocytes (E9.5) revealed loss of Gata1 and many of the known target genes of the SCL-GATA1 complex. ChIP-seq analyses showed that LYL1 exclusively bound a small subset of SCL targets including GATA1. Together, these data show for the first time that Scl and Lyl1 share functional roles in primitive erythropoiesis.

2018-08-13 | GSE103789 | GEO

Mus musculus

Project description:SCL and LMO1 reprogram thymocytes into self-renewing cells.

| PRJNA301090 | ENA

Gene expression profile of human neuroblastoma cell line SHSY-5Y after LMO1 knockdown

Project description:To dissect molecular pathways regulated by LMO1 in neuroblastoma, we performed microarray gene expression profiling in a neuroblastoma cells (SHSY-5Y) after LMO1 knockdown.

2019-11-10 | GSE130747 | GEO

Shared roles for Scl and Lyl1 in murine platelet production and function

Project description:Shared roles for Scl and Lyl1 in murine platelet production and function

| PRJNA514993 | ENA