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

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 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE179083 | GEO | 2021/09/28

REPOSITORIES: GEO

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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

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 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.

2021-09-28 | GSE155763 | 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

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.

2019-06-17 | GSE132078 | 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

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

2019-09-01 | GSE122585 | 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

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

PRC2 is required for acute myeloid leukemias initiated by MLL-AF9

Project description:The transcriptional activating and repressive functions performed by Trithorax and Polycomb group complexes, respectively, are critical for to maintain cellular fates in ontogeny and in cancer. Here we report that leukemias initiated by a Trithorax-related oncogene, MLL-AF9, depend upon the Polycomb Repressive Complex 2 (PRC2) to sustain a transformed cellular state. RNAi mediated suppression of PRC2 subunits is sufficient to inhibit proliferation of MLL-AF9 leukemias, with little impact on growth of non-transformed cells. This requirement is partly due to PRC2-mediated transcriptional repression of several anti-self-renewal regulators, including Cdkn2a. These results suggest that, unlike the classical antagonism generally observed between Polycomb and Trithorax group proteins during development, the activities of these two pathways can cooperate to promote myeloid neoplasia. In order to understand downstream targets of PRC2 complex in MLL-AF9 leukemia, we performed array in murine MLL-AF9/NrasG12D cell line under the condition that two subunits of PRC2(Eed and Suz12) were suppressed by using shRNAs.

2013-07-01 | E-GEOD-34183 | biostudies-arrayexpress

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

Transcription profiling of mouse model of AML - hierarchical maintenance of MLL myeloid leukemia stem cells

Project description:Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells; The genetic programs that promote retention of self-renewing leukemia stem cells (LSCs) at the apex of cellular hierarchies in acute myeloid leukemia (AML) are not known. In a mouse model of human AML, LSCs exhibit variable frequencies that correlate with the initiating MLL oncogene and are maintained in a self-renewing state by a transcriptional sub-program more akin to that of embryonic stem cells (ESCs) than adult stem cells. The transcription/chromatin regulatory factors Myb, Hmgb3 and Cbx5 are critical components of the program and suffice for Hoxa/Meis-independent immortalization of myeloid progenitors when co-expressed, establishing the cooperative and essential role of an ESC-like LSC maintenance program ancillary to the leukemia initiating MLL/Hox/Meis program. Enriched expression of LSC maintenance and ESC-like program genes in normal myeloid progenitors and poor prognosis human malignancies links the frequency of aberrantly self-renewing progenitor-like cancer stem cells to prognosis in human cancer. Experiment Overall Design: Refer to individual Series Experiment Overall Design: This SuperSeries is composed of the following subset Series: Experiment Overall Design: GSE13690: Gene expression profiling of murine MLL leukemias (whole BM) Experiment Overall Design: GSE13692: Expression profiling of MLL-AF10 myeloid leukemia cellular subsets Experiment Overall Design: GSE13693: Gene expression profiling of normal mouse myeloid cell populations

2009-02-21 | E-GEOD-13796 | biostudies-arrayexpress

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