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

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Cell Culture, Bone Marrow

DISEASE(S): Acute Myeloid Leukemia,Acute Leukemia

SUBMITTER: Ashokkumar Jayavelu

LAB HEAD: Prof.Dr.Matthias Mann

PROVIDER: PXD026374 | Pride | 2021-11-04

REPOSITORIES: Pride

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			Action	DRS
	20201211_EXPL2_AsJa_SA_HumanAML_PLCy_sg4_1.raw	Raw
	20201211_EXPL2_AsJa_SA_HumanAML_PLCy_sg4_2.raw	Raw
	20201211_EXPL2_AsJa_SA_HumanAML_PLCy_sg4_3.raw	Raw
	20201211_EXPL2_AsJa_SA_HumanAML_PLCy_sg4_4.raw	Raw
	20201211_EXPL2_AsJa_SA_HumanAML_PLCy_sgNT_1.raw	Raw

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

Project description: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.

2022-01-12 | PXD011251 | Pride

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.

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

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Acute myeloid leukemia (AML) patient blasts and healthy hematopoietic stem and progenitor cell (HSPC) RNA-sequencing Data

Project description:Acute myeloid leukemia (AML) with the t(8;21)(q22;q22) chromosomal translocation is among the most common subtypes of AML and produces the AML1-ETO (AE) oncogenic fusion gene. AML1-ETO expression is critical to for t(8;21) AML leukemogenesis and maintenance. Post-transcriptional regulation of gene expression is often mediated through transcript 3'-untranslated regions (UTR). AML1-ETO uses the 3’UTR of the ETO gene, which is not normally expressed in hematopoietic cells. Therefore, the mechanisms regulating AML1-ETO via the 3’UTR are attractive therapeutic targets. In this study, we examine the regulation of AML1-ETO via the 3’UTR. We demonstrate that AML1-ETO primarily uses a 3.7kb isoform of the ETO 3’UTR in both t(8;21) patients and cell lines. Using a luciferase assay approach, we identify an AML1-ETO 3’UTR fragment between 2.8 and 3.4kb which is negatively regulated, increases expression upon inhibition of microRNA biogenesis, and contains a putative let-7 microRNA target site. We show that let-7b directly represses AML1-ETO through this site. An analysis of The Cancer Genome Atlas AML dataset shows that let-7b and let-7 family miRNA expression is significantly lower in t(8;21) AML than other AMLs. Finally, we demonstrate that let-7b-5p inhibits the proliferation of t(8;21) AML cell lines, rescues expression of AML1-ETO target genes, and promotes differentiation. Our findings establish AML1-ETO as a let-7b target gene and suggest that let-7 based therapeutics may be applied to t(8;21) AML.

2021-12-31 | GSE149237 | GEO

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Project description:Increasing numbers of clinical cohorts have detected CCND2 mutations in acute myeloid leukemia (AML), especially in the subtype of AML with t(8;21) translocation. As known, this AML subtype is characterized by the formation of AML1-ETO fusion gene. However, AML1-ETO fusion gene alone is not sufficient to drive leukemia development, additional mutations are required for leukemogenesis. Here, we aim to investigate whether mutated CCND2 can cooperate with AML1-ETO fusion gene to drive leukemia initiation and progression. In our previous study, the conditional AML1-ETO knock-in mouse model (AML1/ETO mouse), which represented a pre-leukemia stage as myeloproliferative neoplasm phenotype, was established. To confirm whether the AML1-ETO and CCND2 mutation can cooperate to drive leukemia, the mice transduction and transplantation model harboring both AML1-ETO and CCND2 gene (both wildtype and mutant) were established. Upon the assessment of the phenotype, biological features and survival of the mice, only the mice overexpressing the AML1-ETO and CCND2 simultaneously were eventually progressed to leukemia. Besides, compared to mice overexpressing AML-ETO gene alone, mTOR and cell cycle-related pathways were significantly enriched in mice harboring both AML1-ETO and CCND2. And the selective mTOR inhibitor, Everolimus, can reduce the leukemia burden and prolong the survival of this group of mice. In conclusion, we confirmed that introduction of the CCND2 gene into the AML/ETO pre-leukemia mice can trigger the development of leukemia. We also confirmed that CCND2 overexpression resulted in the upregulation of the mTOR pathway and inhibiting the pathway may be a therapeutic agent for this subtype of leukemia.

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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.

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Paired ChIP-Seq studies of Kasumi-1 t(8;21) AML cells

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RNA expression analysis upon JMJD1C depletion

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