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Unleashing cell-intrinsic inflammation as a strategy to kill AML blasts [ChIP-seq]

ABSTRACT: Leukemic blasts are immune cells gone awry. We hypothesized that dysregulation of inflammatory pathways contributes to the maintenance of their leukemic state and can be exploited as a cell-intrinsic, self-directed immunotherapy. To this end, we applied genome-wide screens to discover genetic vulnerabilities in acute myeloid leukemia (AML) cells that are also implicated in inflammatory pathways. We identified the immune modulator interferon regulatory factor 2 binding protein 2 (IRF2BP2) as a selective dependency in AML. We validated AML cell dependency on IRF2BP2 with genetic and protein degradation approaches in vitro and genetically in vivo. Chromatin and global gene expression studies demonstrated that IRF2BP2 represses IL1B/TNFA signaling via NF-KB, and IRF2BP2 perturbation results in an acute inflammatory state leading to AML cell death. These findings elucidate a hitherto unexplored AML dependency, reveal cell-intrinsic inflammatory signaling as a mechanism priming leukemic blasts for regulated cell death, and establish IRF2BP2-mediated transcriptional repression as a mechanism for blast survival.

ORGANISM(S): Homo sapiens

PROVIDER: GSE168647 | GEO | 2022/05/23

REPOSITORIES: GEO

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Unleashing cell-intrinsic inflammation as a strategy to kill AML blasts [RNA-seq]

Project description:Leukemic blasts are immune cells gone awry. We hypothesized that dysregulation of inflammatory pathways contributes to the maintenance of their leukemic state and can be exploited as a cell-intrinsic, self-directed immunotherapy. To this end, we applied genome-wide screens to discover genetic vulnerabilities in acute myeloid leukemia (AML) cells that are also implicated in inflammatory pathways. We identified the immune modulator interferon regulatory factor 2 binding protein 2 (IRF2BP2) as a selective dependency in AML. We validated AML cell dependency on IRF2BP2 with genetic and protein degradation approaches in vitro and genetically in vivo. Chromatin and global gene expression studies demonstrated that IRF2BP2 represses IL1B/TNFA signaling via NF-KB, and IRF2BP2 perturbation results in an acute inflammatory state leading to AML cell death. These findings elucidate a hitherto unexplored AML dependency, reveal cell-intrinsic inflammatory signaling as a mechanism priming leukemic blasts for regulated cell death, and establish IRF2BP2-mediated transcriptional repression as a mechanism for blast survival.

2022-05-23 | GSE168648 | GEO

Unleashing cell-intrinsic inflammation as a strategy to kill AML blasts

Project description:Unleashing cell-intrinsic inflammation as a strategy to kill AML blasts

| PRJNA713326 | ENA

Unleashing cell-intrinsic inflammation as a strategy to kill AML blasts [ChIP-seq]

Project description:Unleashing cell-intrinsic inflammation as a strategy to kill AML blasts [ChIP-seq]

| PRJNA713329 | ENA

Unleashing cell-intrinsic inflammation as a strategy to kill AML blasts [RNA-seq]

Project description:Unleashing cell-intrinsic inflammation as a strategy to kill AML blasts [RNA-seq]

| PRJNA713330 | ENA

RNA sequencing MOLM-13 cells treated with the UBE2N inhibitor UC-764864 or DMSO control

Project description:Dysregulation of innate immune and inflammatory signaling pathways is implicated in various hematologic malignancies. Yet, these pathways have not been systematically examined in acute myeloid leukemia (AML). We report that AML hematopoietic stem and progenitor cells (HSPCs) exhibit a high frequency of dysregulated innate immune-related and inflammatory pathways, referred to as oncogenic immune signaling states. Through gene expression analyses and functional genetic studies, we found that the ubiquitin (Ub) conjugating enzyme UBE2N is required for leukemic cell function in vitro and in vivo by maintaining oncogenicimmune signaling states. Using newly identified small molecule inhibitors of UBE2N as chemical probes, we further revealed the therapeutic efficacy of interfering with UBE2N Ub-conjugating function by preventing ubiquitination of multiple innate immune- and inflammatory-related substrates in AML. Inhibition of UBE2N catalytic function in AML disrupted oncogenic immune signaling by promoting cell death of leukemic HSPCs while sparing healthy cells. Moreover, baseline oncogenic immune signaling states in discrete subsets of primary AML patients exhibited a selective dependency on UBE2N catalytic function. Our study reveals that interfering with UBE2N function abrogates leukemic HSPCs and underscores the dependency of AML cells on UBE2N-dependent oncogenic immune signaling states

2022-09-30 | GSE184889 | GEO

RNA sequencing of MOLM-13 cells transduced with lentivirally expressed UBE2N or control short hairpin RNAs

Project description:Dysregulation of innate immune and inflammatory signaling pathways is implicated in various hematologic malignancies. Yet, these pathways have not been systematically examined in acute myeloid leukemia (AML). We report that AML hematopoietic stem and progenitor cells (HSPCs) exhibit a high frequency of dysregulated innate immune-related and inflammatory pathways, referred to as oncogenic immune signaling states. Through gene expression analyses and functional genetic studies, we found that the ubiquitin (Ub) conjugating enzyme UBE2N is required for leukemic cell function in vitro and in vivo by maintaining oncogenic immune signaling states. Using newly identified small molecule inhibitors of UBE2N as chemical probes, we further revealed the therapeutic efficacy of interfering with UBE2N Ub-conjugating function by preventing ubiquitination of multiple innate immune- and inflammatory-related substrates in AML. Inhibition of UBE2N catalytic function in AML disrupted oncogenic immune signaling by promoting cell death of leukemic HSPCs while sparing healthy cells. Moreover, baseline oncogenic immune signaling states in discrete subsets of primary AML patients exhibited a selective dependency on UBE2N catalytic function. Our study reveals that interfering with UBE2N function abrogates leukemic HSPCs and underscores the dependency of AML cells on UBE2N-dependent oncogenic immune signaling states

2022-09-30 | GSE184852 | GEO

Inflammatory conversion of normal hematopoietic stem and progenitor cells by acute myeloid leukemia derived extracellular vesicles in vivo

Project description:Inflammation in the bone marrow (BM) microenvironment is a constitutive component of acute myeloid leukemia (AML) pathogenesis. Studies have demonstrated that leukemic blasts propagate acute inflammation in the AML niche. Our recent studies in a congenic AML model suggest residual healthy hematopoietic stem and progenitor cells (HSPCs) participate in the inflammatory crosstalk. However, the underlying mechanism that drives the inflammatory conversion of HSPCs remains unclear. Here, we ask whether AML-derived extracellular vesicles (EV-AML) can convert HSPCs into an inflammatory active state in vivo. Using EV-AML purified from inducible (i)MLL-AF9 AML blasts (AF9-EV-AML), we challenged healthy C57BL/6J mice with serial injections of AF9-EVAML and analyzed HSPCs transcriptome. We show that HSPC transcriptome corroborates the enrichment of inflammatory and innate immune responses in EVAML-challenged BM HSPCs compared to controls. Our findings suggest that AML converts HSPCs into an inflammatory hub via EVAML in the AML niche.

2024-04-24 | GSE239307 | GEO

Normal hematopoietic stem and progenitor cells in murine acute myeloid leukemia model in vivo

Project description:Bone marrow inflammation has been linked to acute myeloid leukemia (AML) progression. Studies have demonstrated that leukemic blasts propagate acute inflammation in the AML niche, but the involvment of normal hematopoietic stem and progenitor cells (HSPCs) in the inflammatory crosstalk is not well understood. To better model compartmental inflammation in AML, we first established a highly penetrant, immunocompetent, fully congenic system. Using the monoblastic AML cell line C1498 (CD45.2+), we grafted non-condition C57BL/6J (CD45.1) mice, avoiding changes in BM niche function. We then fluoresence-activated cell sorting (FACS)-sorted residual normal HSPCs for single-cell RNA-sequencing analysis. We show that residual normal HSPCs from C1498-grafted mice expresses key inflammatory signature and are enriched in inflammatory signaling related pathways. Overall, we show that normal HSPCs engages in inflammatory signaling in AML niche.

2024-01-01 | GSE238091 | GEO

Bortezomib suppresses self-renewal and leukemogenesis of leukemia stem cell by NF-ĸB-dependent inhibition of cyclin dependent kinase 6 in MLL-rearranged myeloid leukemia

Project description:Acute myeloid leukemia (AML) with chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukemia (MLL) is an aggressive subtype with low overall survival. MLL rearrangements rapidly transform hematological stem and progenitor cell (HSPC) to leukemia stem cell (LSC). Bortezomib (Velcade) is used widely in hematological malignancies. However, it is still unknown whether bortezomib possesses anti-self-renewal and anti-leukemogenesis of LSC in AML with MLL rearrangements. Here, we found that bortezomib inhibited cell proliferation, induced apoptosis, and decreased colony formation in leukemic cell lines, primary AML blasts, and MLL-AF9-transformed murine leukemic blasts. Besides, bortezomib reduced the frequency and function of LSC, inhibited the progression, and prolonged

2022-08-10 | GSE157702 | GEO

Aberrant expressed genes in AML

Project description:Acute myeloid leukemia (AML) is one of the most common and deadly forms of hematopoietic malignancies. We hypothesized that microarray studies could identify aberrantly expressed genes selectively expressed in AML blasts, believing that these genes may be potential therapeutic targets for adoptive T-cell strategies We compared gene expression profiles between leukemic blasts from 30 AML patients (this series and GSE9476) and prepublished samples of normal hematopoietic cells from healthy donors (N=17, GSE9476) and testis samples (N=2, GSE1133).

2012-04-16 | E-GEOD-37307 | biostudies-arrayexpress

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