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

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE184852 | GEO | 2022/09/30

REPOSITORIES: GEO

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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

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

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

Ubiquitination of the spliceosome auxiliary factor hnRNPA1 by TRAF6 links chronic innate immune signaling with hematopoietic defects and myelodysplasia

Project description:Toll-like receptors (TLR) activation contributes to premalignant hematologic conditions, such as myelodysplastic syndromes (MDS). TRAF6, a TLR effector with ubiquitin (Ub) ligase activity, is overexpressed in MDS hematopoietic stem/progenitor cells (HSPCs). We found that TRAF6 overexpression in mouse HSPC results in impaired hematopoiesis and bone marrow failure. Using a global Ub screen, we identified hnRNPA1, an RNA-binding protein and auxiliary splicing factor, as a substrate of TRAF6. TRAF6 ubiquitination of hnRNPA1 regulated alternative splicing of Arhgap1, which resulted in activation of the GTP-binding Rho family protein Cdc42 and accounted for hematopoietic defects in TRAF6-expressing HSPCs. These results implicate Ub signaling in coordinating RNA processing by TLR pathways during an immune response and in premalignant hematologic diseases, such as MDS.

2016-12-20 | GSE64542 | GEO

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

Acute myeloid leukemia cells functionally compromise hematopoietic stem/progenitor cells inhibiting normal hematopoiesis through the release of extracellular vesicles

Project description:Acute myeloid leukemia (AML) is an aggressive and heterogeneous clonal disorder of hematopoietic stem/progenitor cells (HSPCs). It is not well known how leukemia cells alter hematopoiesis promoting tumor growth and leukemic niche formation. In this study, we investigated how AML deregulates the hematopoietic process of HSPCs through the release of extracellular vesicles (EVs). First, we found that AML cells released a heterogeneous population of EVs (AML-EVs) containing microRNAs involved in AML pathogenesis. Notably AML-EVs were able to influence the fate of HSPCs modifying their transcriptome. In fact, a gene expression profile of AML-EV-treated HSPCs identified approximately 923 down and 630 up-regulated genes involved in hematopoiesis/differentiation, inflammatory cytokine production and cell movement. Indeed, most of the downregulated genes are targeted by AML-EV-derived miRNAs. Furthermore, we demonstrated that AML-EVs were able to affect HSPCs phenotype, modifying several biological functions, such as inhibiting cell differentiation and clonogenicity, activating inflammatory cytokine production and compromising cell movement. Indeed, a redistribution of HSPC populations was observed in AML-EV treated cells with a significant increase in the frequency of common myeloid progenitors and a reduction in granulocyte-macrophage progenitors and megakaryocyte-erythroid progenitors. This effect was accompanied by a reduction in HSPC colony formation. AML-EV treatment of HSPCs increased the levels of CCL3, IL1B and CSF2 cytokines, involved in the inflammatory process and in cell movement, and decreased CXCR4 expression associated with a reduction of SDF-1 mediated-migration. In conclusion, this study demonstrates the existence of a powerful communication between AML cells and HSPCs, mediated by EVs, which suppresses normal hematopoiesis and potentially contributes to create a leukemic niche favorable to neoplastic development.

2022-03-11 | GSE189492 | GEO

Targeting MDM2-induced p53 upregulation to enhance anti-leukemia immunity post allogeneic stem cell transplantation

Project description:Relapse after allo-HCT is a major cause of death of AML patients and results from immune evasion of AML blasts. Dysfunction of the p53 signaling pathway is frequent in AML and often caused by upregulation of the central p53 negative regulator Murine Double Minute 2 (MDM2). Besides its oncogenic effects p53 also regulates immune function and immune surveillance of solid cancer. We hypothesize that p53 also controls immune-related genes in AML cells and that p53 reactivation via MDM2-inhibition may enhance the immunogenicity of AML cells to allogeneic T cells.

2022-09-20 | GSE158103 | GEO

TRAF6 is a tumor suppressor in AML by directly targeting MYC oncogenic activity [RNA-Seq]

Project description:Clonal hematopoiesis of indeterminant potential (CHIP) is an aging-associated condition characterized by the clonal outgrowth of self-renewing cells that acquire specific mutations. One of the most frequent mutations in CHIP targets the methylcytosine dioxygenase TET2, also observed in number of myeloid neoplasms 1,2. Although individuals with CHIP are healthy, they are at an increased risk of developing hematopoietic malignancies. These findings indicate that additional alterations are needed for the transition from a pre-leukemic (CHIP) stage to frank leukemia, although the identity of such molecular events remains poorly characterized. To identify signaling states that cooperate with CHIP mutant cells we used an in vivo RNAi screening approach. One of the most prominent genes identified was the ubiquitin ligase TRAF6. We demonstrate that TRAF6 is repressed in a subset of acute myeloid leukemia (AML) and myeloproliferative neoplasm (MPN) patients. Loss of TRAF6 in pre-leukemic HSPC results in overt AML/MPN and is associated with induction of MYC-dependent leukemic stem cell signatures. TRAF6 represses MYC activity at enhancers due to the ubiquitination of MYC on Lysine (K)148. Ubiquitination of MYC on K148, does not affect protein stability but rather antagonizes acetylation of MYC on the same lysine and suppresses MYC oncogenic activity by preventing its DNA binding. Our results identify a novel tumor suppressor function for TRAF6 and demonstrate a novel mode of regulation of MYC oncogenic activity

2022-01-01 | GSE189172 | 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

Unleashing cell-intrinsic inflammation as a strategy to kill AML blasts [ChIP-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 | GSE168647 | GEO

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