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Single cell RNA-seq analysis of transcriptomics in WT and E2-KO, G12D and G12D/E2-KO HSPCs from mouse bone marrow

ABSTRACT: Cancers develop from the accumulation of somatic mutations, yet it remains unclear how oncogenic lesions cooperate to drive cancer progression. Using a mouse model harboring NRasG12D and EZH2 mutations that recapitulates leukemic progression, we employ single-cell RNA sequencing to map cellular composition and gene expression alterations in healthy or diseased bone marrows underlying leukemia progression. At cellular levels, while NRasG12D induces myeloid-biased differentiation and EZH2-deficiency impairs myeloid maturation, they cooperate to promote myeloid expansion with dysregulated transcriptional programs. At gene levels, NRasG12D and EZH2-deficiency independently or synergistically control gene expression in single cells. We integrate results from histopathology, flow cytometry, leukemia repopulation, and leukemia-initiating cell assays to validate transcriptome-based cellular profiles. We use this resource to relate developmental hierarchies to leukemia phenotypes, evaluate oncogenic cooperation at single-cell levels, and identify new regulators of leukemia-initiating cells. Our studies establish an integrative approach to capture the kinetics of cancer evolution in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE155763 | GEO | 2021/09/28

REPOSITORIES: GEO

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Whole exome sequencing analysis of bone marrow c-Kit+ leukemia cells in Nras-G12D with Ezh2 KO (E2-KO) mice

Project description:Epigenetic gene regulation and metabolism are highly intertwined, yet little is known whether and how altered epigenetics influences cellular metabolism in cancer progression. Here we show that EZH2 and NRasG12D mutations cooperatively induce progression of myeloproliferative neoplasms to fully penetrant, transplantable and lethal myeloid leukemias in mouse. EZH1, an EZH2 homolog, is indispensable for EZH2-deficient leukemia-initiating cells (LICs) and constitutes an epigenetic vulnerability. BCAT1, the first enzyme catalyzing transamination of branched-chain amino acids (BCAAs), is repressed by EZH2 in normal hematopoiesis and aberrantly activated in EZH2-deficient myeloid neoplasms in mouse and human. Enhanced BCAT1 promotes BCAA production in LICs ex vivo and in vivo, resulting in activated mTOR signaling. Genetic and pharmacological inhibition of BCAT1 selectively impairs EZH2-deficient LICs and constitutes a metabolic vulnerability. These findings establish an example how epigenetic alterations modify metabolic adaptation in myeloid transformation and provide a rationale for targeting the epigenetic and metabolic liabilities of cancer-initiating cells.

2019-09-01 | GSE122585 | GEO

ATAC-seq analysis in bone marrow LSK cells in WT, G12D, Ezh2-KO and G12D with Ezh2-KO (G12D_Ezh2-KO) mice

2019-06-17 | GSE132077 | GEO

RNA-seq analysis of transcriptomic changes in bone marrow LSK cells in WT, G12D, Ezh2-KO and G12D with Ezh2-KO (G12D_Ezh2-KO) mice [RNA-seq]

2019-06-17 | GSE132079 | GEO

ChIP-seq analysis of H3K4me3,H3K27ac and H3K27me3 in bone marrow LSK cells in WT, G12D, Ezh2-KO and G12D with Ezh2-KO (G12D_Ezh2-KO) mice

2019-06-17 | GSE132078 | GEO

RNA-seq analysis of transcriptomic changes in control (shLuc) and GEM knockdown (shGem) bone marrow LSK cells

Project description:Cancers develop from the accumulation of somatic mutations, yet it remains unclear how oncogenic lesions cooperate to drive cancer progression. Using a mouse model harboring NRasG12D and EZH2 mutations that recapitulates leukemic progression, we employed single-cell RNA sequencing to map cellular composition and gene expression alterations in healthy or diseased bone marrows during leukemogenesis. At cellular level, NRasG12D induces myeloid-biased differentiation and EZH2-deficiency impairs myeloid cell maturation, whereas they cooperate to promote myeloid expansion with dysregulated transcriptional programs. At gene level, NRasG12D and EZH2-deficiency independently and synergistically control gene expression in single cells. We integrated results from histopathology, leukemia repopulation, and leukemia-initiating cell assays to validate transcriptome-based cellular profiles. We used this resource to relate developmental hierarchies to leukemia phenotypes, evaluated oncogenic cooperation at single-cell and single-gene levels, and identified GEM as a new regulator of leukemia-initiating cells. Our studies establish an integrative approach to deconvolute cancer evolution in vivo.

2021-09-28 | GSE179083 | GEO

Global Gene Expression of hematopoietic stem cells expressing endogenous NrasG12D/G12D, NrasG12D/+, Nras+/+

Project description:Oncogenic NRAS mutations are frequently identified in human myeloid leukemias. In mice, expression of endogenous oncogenic Nras (NrasG12D/+) in hematopoietic cells leads to expansion of myeloid progenitors, increased long-term reconstitution of bone marrow cells, and a chronic myeloproliferative neoplasm (MPN). However, acute expression of NrasG12D/+ in a pure C57BL/6 background does not induce hyperactivated GM-CSF signaling or increased proliferation in myeloid progenitors. It is thus unclear how NrasG12D/+ signaling promotes leukemogenesis. Here we show that hematopoietic stem cells (HSCs) expressing NrasG12D/+ serve as MPN initiating cells. They undergo moderate hyperproliferation with increased self-renewal. The aberrant NrasG12D/+ HSC function is associated with hyperactivation of ERK1/2 in HSCs. Conversely, downregulation of MEK/ERK by pharmacological and genetic approaches attenuates the cycling of NrasG12D/+ HSCs and prevents the expansion of NrasG12D/+ HSCs and myeloid progenitors. Our data delineate critical mechanisms of oncogenic Nras signaling in HSC function and leukemogenesis. three NrasG12D/G12D HSCs samples, three NrasG12D/+ HSCs samples, two Nras+/+ HSCs control samples.

2013-05-29 | E-GEOD-46948 | biostudies-arrayexpress

Global Gene Expression of hematopoietic stem cells expressing endogenous NrasG12D/G12D, NrasG12D/+, Nras+/+

2013-05-29 | GSE46948 | GEO

Gene expression changes in NRASG12D, NUP98-NSD1 and NUP98-NSD1+NRASG12D transformed mouse bone marrow cells (in vitro).

Project description:NUP98-NSD1 positive Acute myeloid leukemia (AML) frequently occurs within the pediatric karyotypic normal(CN)-AML cohort. It is often associated with mutations in genes like FLT3, NRAS, WT1 and MYC. Here we have studied the role of NUP98-NSD1 fusion and NRASG12D in leukemia initiation and progression.

2020-10-01 | GSE152244 | GEO

RNA sequencing expression analysis of murine MLL-AF9;NRAS acute myeloid leukemia cells silenced for E2-2.

Project description:We investigated the role of the transcriptional regulators Id2 and E2-2 (encoded by Tcf4) in the context of MLL-rearranged acute myeloid leukemia (AML). Using an AML mouse model driven by a Tet-off inducible MLL-AF9 allele co-expressed with oncogenic NRASG12D, we demonstrated that MLL-AF9 regulates the E protein pathway by suppressing Id2, while activating the expression of its target E2-2. Moreover, we found that Id2 over-expression in MLL-AF9 AML cells results inhibition of leukemia growth, loss of leukemia stem cell-associated gene expression pattern and induction of differentiation. E2-2 silencing phenocopies Id2 overexpression in MLL-AF9-AML cells. To study the gene expression changes associated with E2-2 depletion in the context of MLL-rearranged AML, RNA sequencing analysis was performed on MLL-AF9;NRAS AML cells transduced with vectors expressing hairpins against E2-2 (shTcf4#654 and shTcf4#3646) or a control hairpin against Renilla luciferase (shRen). Primary AMLs driven by MLL/AF9 expression linked to cherry reporter, in association with oncogenic NRASG12D (MLL/AF9;NRAS) were generated by reconstituting lethally irradiated congenic mice with fetal liver cells co-transduced with the MSCV-MLL/AF9-IRES-cherry retroviral vector and a second vector co-expressing NRASG12D together with luciferase (MSCV-luciferase-IRES-NRASG12D). RNA sequencing analysis sequencing analysis was performed on MLL-AF9;NRAS AML cells transduced in vitro with vectors expressing hairpins against E2-2 (shTcf4#654 and shTcf4#3646) or a control hairpin against Renilla luciferase (shRen) linked to the reporter GFP. Viable GFP-positive cells were FACS-sorted 2 days after transduction and used for RNA sequencing analysis. Two independent biological replicates of the experiment were used for the RNA sequencing (9-5-14 and 14-4-14).

2016-06-29 | E-GEOD-80745 | biostudies-arrayexpress

Gene expression profiles of mouse BM LSKs, wild-type as well as Ezh2 KO mouse CML leukemia initiating cells (LICs)

Project description:Tyrosine kinase inhibitors (TKIs) have revolutionized chronic myelogenous leukemia (CML) management. Disease eradication, however, is hampered by innate resistance of leukemia initiating cells (LICs) to TKI-induced killing, which also provides the basis for subsequent emergence of TKI-resistant mutants. We report that EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), is overexpressed in CML LICs, required for colony formation, and survival and cell cycle progression of CML cell lines. A critical role for Ezh2 is supported by genetic studies in a mouse CML model. Inactivation of Ezh2 in conventional conditional mice and through CRISPR/Cas9-mediated gene editing prevents initiation and maintenance of disease and survival of LICs, irrespective of BCR/ABL1 mutational status, and extends survival. Expression of the Ezh2 homolog Ezh1 is reduced in Ezh2-deficient CML LICs, creating a scenario resembling complete loss of PRC2. EZH2-dependence of CML LICs raises prospects for improved therapy of TKI-resistant CML and/or eradication of disease by addition of EZH2 inhibitors.

2016-08-18 | GSE85744 | GEO

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