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AML1-ETO induced leukemia stem cell self-renewal depends on Plcg1

ABSTRACT: High-resolution proteomic analysis of acute myeloid leukemia (AML) stem cells identified phospholipase C- and Ca++-signaling pathways to be differentially regulated in AML1-ETO (AE) driven leukemia. Phospholipase C gamma 1 (Plcg1) could be identified as a direct target of the AE fusion. Genetic Plcg1 inactivation abrogated disease initiation by AE, reduced intracellular Ca++-release and inhibited AE-driven self-renewal programs. In AE-induced leukemia, Plcg1 deletion significantly reduced disease penetrance, number of leukemia stem cells and abrogated leukemia development in secondary recipient hosts. In human AE-positive leukemic cells inactivation of Plcg1 reduced colony formation and AML development in vivo. In contrast, Plcg1 was dispensable for maintenance of murine and human hematopoietic stem- and progenitor cells (HSPCs). Pharmacologic inhibition of Ca++-signaling downstream of Plcg1 resulted in impaired proliferation and self-renewal capacity in AE-driven AML. Thus, the Plcg1 pathway represents a novel specific vulnerability of AE-driven leukemia and poses an important new therapeutic target.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Primary Cell, Stem Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Joanna Kirkpatrick

LAB HEAD: Florian H. Heidel

PROVIDER: PXD011251 | Pride | 2022-01-12

REPOSITORIES: Pride

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AML1-ETO induced leukemia stem cell self-renewal depends on Plcg1

Project description:Leukemia stem cells are characterized by aberrant self-renewal capacity. Targeting oncogenic fusions that mediate this aberrant self-renewal capacity remains a therapeutic challenge. The t(8;21) translocation, resulting in the oncogenic fusion AML1-ETO (AE, RUNX1-RUNXT1) is among the most common chromosomal rearrangements found in acute myeloid leukemia (AML). By conducting high-resolution proteomic analysis on myeloid leukemia stem cells we identified Phospholipase C- and Ca++-signaling pathways to be differentially regulated in AE/t(8;21) AML. Phospholipase C gamma 1 (Plcg1) was specifically, and highly expressed in t(8;21) AML and could be identified as a direct target of the AML1(RUNX1)-ETO fusion. Genetic inactivation of Plcg1 resulted in abrogation of disease initiation by AE, reduction of intracellular Ca++ release and loss of AE-driven self-renewal programs. Plcg1 deletion after onset of AE-induced leukemia significantly reduced disease penetrance, number of leukemia stem cells and resulted in abrogation of leukemia development in secondary recipients. Inactivation of Plcg1 in human AE-positive AML cells by RNAi reduced colony formation and AML development in vivo. In contrast, Plcg1 was dispensable for steady state hematopoiesis and maintenance of murine and human hematopoietic stem cells (HSC). Translationally, we used pharmacologic inhibition of Ca++ signaling downstream of Plcg1 in AE-driven AML and this resulted in impaired proliferation and self-renewal capacity. The Plcg1 pathway represents a novel, specific vulnerability of AE-driven leukemia and represents an important new therapeutic target.

2019-09-02 | GSE122062 | GEO

AML1-ETO induced leukemia stem cell self-renewal depends on Plcg1

2022-05-02 | GSE120828 | GEO

PLCG1 is required for AML1-ETO leukemia stem cell self-renewal

Project description:In an effort to identify novel drugs targeting fusion-oncogene induced acute myeloid leukemia (AML), we performed high-resolution proteomic analysis. In AML1-ETO (AE) driven AML we uncovered a deregulation of phospholipase C (PLC) signaling. We identified PLCgamma 1 (PLCG1) as a specific target of the AE fusion protein which is induced after AE binding to intergenic regulatory DNA elements. Genetic inactivation of PLCG1 in murine and human AML inhibited AML1-ETO dependent self-renewal programs, leukemic proliferation, and leukemia maintenance in vivo. In contrast, PLCG1 was dispensable for normal hematopoietic stem- and progenitor cell function. These findings are extended to and confirmed by pharmacologic perturbation of Ca++-signaling in AML1-ETO AML cells, indicating that the PLCG1 pathway poses an important therapeutic target for AML1-ETO positive leukemic stem cells.

2021-11-04 | PXD026374 | Pride

TAF1 is critical for AE driven leukemogenesis [ATAC-seq]

Project description:TAF1 is essential for AE driven leukemogenesis. Depletion of TAF1 impairs the recruitment of AE to its target genes, interfereing with its control of gene expression. The bromodomains of TAF1 associate with K43 acetylated AE and this association plays a role in the proliferationof AE expressing AML cells.

2019-09-11 | GSE134018 | GEO

TAF1 is critical for AE driven leukemogenesis [RNA-seq]

Project description:TAF1 is essential for AE driven leukemogenesis. Depletion of TAF1 impairs the recruitment of AE to its target genes, interfering with its control of gene expression. The bromodomains of TAF1 associate with K43 acetylated AE and this association plays a role in the proliferation of AE expressing AML cells.

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TAF1 is critical for AE driven leukemogenesis [ChIP-seq]

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AML1-ETO-induced FOXO1 activates a self-renewal program in pre-leukemia stem cells

Project description:Blocking the self-renewal of pre-leukemia stem cells could prevent AML relapse. In this study we show that FOXO1 is an essential self-renewal factor in leukemic and pre-leukemic cells expressing the t(8;21)-associated oncogene AML1-ETO (AE). FOXO1 is consistently upregulated in t(8;21) AML and functions as a critical oncogenic mediator rather than a tumor suppressor. Expression of FOXO1 in human CD34+ cells promotes a pre-leukemic state, partially phenocopying the cellular and transcriptional effects of AE expression. The DNA binding ability of FOXO1 is essential for these features. AE and FOXO1 co-occupy the majority of their binding sites, whereby FOXO1 binds to multiple crucial self-renewal genes and is required for their activation. In concordance with this observation, loss of FOXO1 inhibits the long-term proliferation and clonogenicity of AE cells. Thus, increased FOXO1 represents a new mechanism for acquiring aberrant self-renewal by pre-leukemia stem cells and provides a novel target for therapeutic intervention.

2017-10-30 | GSE80773 | GEO

LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8;21) AML [RNA-seq]

Project description:Transcription factors (TFs) play critical roles in hematopoiesis, and their aberrant expression can lead to various types of leukemia. The t(8;21) leukemogenic fusion protein AML1-ETO (AE) is the most common fusion protein in acute myeloid leukemia and can enhance hematopoietic stem cell renewal while blocking differentiation. A key question in understanding AE-mediated leukemia is what determines the choice of AE to activate self-renewal genes or repress differentiation genes. Toward the resolution of this problem, we earlier showed that AE resides in the stable AETFC complex and that its components co-localize on up- or down-regulated target genes and are essential for leukemogenesis. In the current study, using biochemical and genomic approaches, we show that AE-containing complexes are heterogeneous, and that assembly of the larger AETFC (containing AE, HEB, E2A, LYL1, LMO2 and LDB2) requires LYL1. Furthermore, we provide strong evidence that the LYL1-containing AETFC preferentially binds to active enhancers and promotes AE-dependent gene activation. Moreover, we show that coactivator CARM1 interacts with AETFC and facilitates gene activation by AETFC. Collectively, this study describes a novel role of oncoprotein LYL1 in AETFC assembly and gene activation by recruiting CARM1 to chromatin for AML cell survival.

2022-11-10 | GSE207233 | GEO

LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8;21) AML [CHIP-seq]

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Oncogene EVI1 Drives Acute Myeloid Leukemia Via a Targetable Interaction with CTBP2

Project description:Acute myeloid leukemia (AML) driven by the activation of EVI1 due to chromosome 3q26/MECOM rearrangements is incurable with current chemotherapy regimens. Insight into the mechanism by which EVI1 drives myeloid transformation is needed to target EVI1 in those leukemias. Here we demonstrate recurrent interaction of CTBP1/2 with a unique PLDLS motif in EVI1, which is indispensable for leukemic transformation of 3q26/MECOM rearranged AML. A PLDLS competitor construct outcompetes EVI1 to CTBP1/2 binding and inhibits AML proliferation in xenotransplant models. This proof-of-concept study opens the possibility to target one of the most incurable forms of AML using specific inhibitors directed to EVI1/CTBP1/2 interaction. Our findings have important implications for other tumour types with aberrant expression of EVI1 or other oncogenic transcription factors that also depend on CTBP1/2 interaction.

2023-07-13 | PXD043333 | Pride

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