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Type I Innate Lymphoid Cells Control Leukemia Stem Cell Fate and Limit Development of Acute Myeloid Leukemia [1]

ABSTRACT: Type I innate lymphoid cells (ILC1s) are critical regulators of inflammation and immunity in mammalian tissues. However, their functional roles in cancer are largely undefined. We found that a high concentration of normal murine ILC1s induced leukemia stem cell (LSC) apoptosis. At a lower concentration, ILC1s prevented LSCs from differentiating into leukemia progenitors and promoted their differentiation into non-leukemic cells, thus blocking the production of terminal myeloid blasts. All of these effects, which required ILC1s to produce interferon-γ after cell–cell contact with LSCs, converged to suppress leukemogenesis in vivo. Conversely, ILC1s’ anti-leukemia potential waned when JAK-STAT and PI3K-AKT signaling was inhibited. The relevant anti-leukemic properties of normal ILC1s were operative in humans and impaired in AML patients. Collectively, our findings reveal crucial functions of ILC1s as anti-cancer immune cells seemingly suitable for AML immunotherapy, and provide a new potential strategy to treat AML and/or prevent relapse of the disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE198781 | GEO | 2022/03/19

REPOSITORIES: GEO

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Type I Innate Lymphoid Cells Control Leukemia Stem Cell Fate and Limit Development of Acute Myeloid Leukemia [2]

Project description:Type I innate lymphoid cells (ILC1s) are critical regulators of inflammation and immunity in mammalian tissues. However, their functional roles in cancer are largely undefined. We found that a high concentration of normal murine ILC1s induced leukemia stem cell (LSC) apoptosis. At a lower concentration, ILC1s prevented LSCs from differentiating into leukemia progenitors and promoted their differentiation into non-leukemic cells, thus blocking the production of terminal myeloid blasts. All of these effects, which required ILC1s to produce interferon-γ after cell–cell contact with LSCs, converged to suppress leukemogenesis in vivo. Conversely, ILC1s’ anti-leukemia potential waned when JAK-STAT and PI3K-AKT signaling was inhibited. The relevant anti-leukemic properties of normal ILC1s were operative in humans and impaired in AML patients. Collectively, our findings reveal crucial functions of ILC1s as anti-cancer immune cells seemingly suitable for AML immunotherapy, and provide a new potential strategy to treat AML and/or prevent relapse of the disease.

2022-03-19 | GSE198782 | GEO

Proteomics analysis for RBM17 in acute myeloid leukemia

Project description:Acute myeloid leukemia (AML) patients suffer from chemo-resistance, high relapse frequency, and low overall survival rate, outcomes driven by leukemic stem cells (LSCs). Understanding the molecular mechanisms that support these primitive leukemic cells is crucial for developing effective AML therapeutics. In the present study, we demonstrate that upregulation of the splicing factor RBM17 preferentially marks and sustains the primitive compartment of AML. We performed shotgun proteomics to characterize the proteome changes upon RBM17 knockdown in AMl cells. In addition, we used proteomics to analyze the proteome changes after knockdown of EIF4A2, a direct splicing substrate of RBM17 in AML cells.

2022-08-12 | PXD026780 | Pride

Effect of sgRNA-mediated disruption of GLUT1 on gene expression on c-Kit+ MLL::AF9 leukemia cells

Project description:Acute myeloid leukemia (AML) is initiated and propagated by leukemia stem cells (LSCs), a self-renewing population of leukemia cells. Here we performed an in vivo CRISPR screen and identified the facilitated glucose transporter type 1 (GLUT1) as a critical metabolic dependency for murine MLL::AF9 LSCs. GLUT1 disruption by genetic ablation or by pharmacological inhibition with BAY-876 led to suppression of leukemia progression and improved survival in an MLL::AF9 mouse model of AML. Glut1 inhibition further resulted in glycolytic suppression, decreased levels of tricarboxylic cycle intermediates, and elevated levels of amino acids. These changes in metabolic profile coincided with increased autophagic activity and differentiation of AML cells. Notably, dual inhibition of GLUT1 and oxidative phosphorylation exhibited synergistic anti-leukemic effects in human AML cells. Collectively, these findings increase our understanding of how murine LSCs are metabolically regulated and highlight GLUT1 inhibition as a promising therapeutic adjuvant approach in AML.

2022-07-28 | GSE209636 | GEO

All-trans retinoic acid enhances, and a pan-RAR antagonist counteracts, the stem cell promoting activity of EVI1 in acute myeloid leukemia

Project description:Ecotropic virus integration site 1 (EVI1), whose overexpression characterizes a particularly aggressive subtype of acute myeloid leukemia (AML), enhanced anti-leukemic activities of all-trans retinoic acid (atRA) in cell lines and patient samples. However, the drivers of leukemia formation, therapy resistance, and relapse are leukemic stem cells (LSCs), whose properties were hardly reflected in these experimental setups. The present study was designed to address the effects of, and interactions between, EVI1 and retinoids in AML LSCs. We report that Evi1 reduced the maturation of leukemic cells and promoted the abundance, quiescence, and activity of LSCs in an MLL-AF9-driven mouse model of AML. atRA further augmented these effects in an Evi1 dependent manner. EVI1 also strongly enhanced atRA regulated gene transcription in LSC enriched cells. One of their jointly regulated targets, Notch4, was an important mediator of their effects on leukemic stemness. In vitro exposure of leukemic cells to a pan-RAR antagonist caused effects opposite to those of atRA. In vivo antagonist treatment delayed leukemogenesis and reduced LSC abundance, quiescence, and activity in Evi1high AML. Key results were confirmed in human myeloid cell lines retaining some stem cell characteristics as well as in primary human AML samples. In summary, our study is the first to report the importance of EVI1 for key properties of AML LSCs. Furthermore, it shows that atRA enhances, and a pan-RAR antagonist counteracts, the effects of EVI1 on AML stemness, thus raising the possibility of using RAR antagonists in the therapy of EVI1high AML.

2019-12-13 | GSE123255 | GEO

Transcription profiling of human MLL-AF10 myeloid leukemia cellular subsets

Project description:Leukemia cells from mice with MLL-AF10 AML were fractionated into separate sub-populations on the basis of c-kit expression, which correlates with MLL LSC frequency (Somervaille and Cleary, 2006). The sorted AML sub-populations exhibited substantial differences in their frequencies of AML CFCs/LSCs (mean 14-fold) and morphologic features, consistent with a leukemia cell hierarchy with maturation through to terminally differentiated neutrophils. Experiment Overall Design: Leukemic splenocytes from four mice with MLL-AF10 AML were sub-fractionated in to c-kit high and c-kit negative sub-populations by FACS.

2009-02-21 | E-GEOD-13692 | biostudies-arrayexpress

RNA-seq of LSC-like, non-LSC and Mature populations from human AML patient samples

Project description:Acute myeloid leukemia (AML) is a highly heterogeneous disease and reliable detection of leukemic stem cells (LSCs) across genetic subclasses has proven difficult. We aimed to transcriptionally characterize LSCs specifically in monocyte-like AML (Mono-AML) and and primitive-like AML (Prim-AML) samples using cell surface markers. We used CD64+CD11b+ to define Mature blasts and labelled the rest as Immature. To further enrich for LSC-like cells in the Immature blasts in both Mono- and Prim-AML samples, we included GPR56, a marker for LSCs. We performed RNA sequencing on the FACS-sorted LSC-like and Mature cells from 23 AML patients.

2023-03-01 | E-MTAB-11976 | biostudies-arrayexpress

Msi2 sustains the MLL leukemia stem cell regulatory program

Project description:Leukemia stem cells (LSCs) are found in most aggressive myeloid diseases and contribute to therapeutic resistance. Genetic and epigenetic alterations cause a dysregulated developmental program in leukemia. The MSI2 RNA binding protein has been previously shown to predict poor survival in leukemia. We demonstrate that the conditional deletion of Msi2 results in delayed leukemogenesis, reduced disease burden and a loss of LSC function. Gene expression profiling of the Msi2 ablated LSCs demonstrates a loss of the HSC/LSC and an increase in the differentiation program. The gene signature from the Msi2 deleted LSCs correlates with survival in AML patients. MSI2’s maintains the MLL self-renewal program by interacting with and retaining efficient translation of Hoxa9, Myc and Ikzf2. We further demonstrate that shRNA depletion of the MLL target gene Ikzf2 also contributes to MLL leukemia cell survival. Our data provides evidence that MSI2 controls efficient translation of the oncogenic LSC self-renewal program and a rationale for clinically targeting MSI2 in myeloid leukemia. RNA-Seq was performed on sorted c-Kit high leukemic cells from 2 Msi2 -/- and 2 Msi2 f/f mice.

2015-01-15 | E-GEOD-64545 | biostudies-arrayexpress

Distinct leukemogenic mechanism of acute promyelocytic leukemia based on genomic structure of PML-RARα fusion gene

Project description:Leukemic stem cells (LSCs) of acute myeloid leukemia (AML) are enriched in CD34+CD38- fraction, and self-renewing LSCs hierarchically organize and maintain the AML populations. In acute promyelocytic leukemia (APL), which is driven by PML-RARα fusion genes, the presence of LSCs has long been unidentified, due to the difficulty of efficient reconstitution of human APL in the immunodeficient mice. Here, we show that LSCs of short type isoform APL, subtype of APL defined by different breakpoint of PML gene, concentrate in CD34+CD38- fraction and express T cell immunoglobulin mucin-3 (TIM-3) as in other non-APL AML. Short type APL cells exhibited distinct gene expression signatures including LSCs-related genes from other types of APL. Moreover, CD34+CD38-TIM-3+ short type APL cells efficiently reconstituted huma APL in xenograft models with high penetration, whereas CD34- more differentiated APL cells did not. Furthermore, CD34+CD38-TIM-3+ short type APL cells also reconstituted leukemia in the serial transplantation. Thus, short type APL is showing hierarchically organized by self-renewing APL-LSCs same as in other types of AML. The identification of LSCs in a subset of APL and establishment of efficient patient derived xenograft model would contribute to further understanding of APL leukemogenesis and devising individual treatment for eradication of APL LSCs.

2022-07-05 | GSE207432 | GEO

Dormant leukemia stem cells reinforced by chemotherapy drive early treatment failure in acute myeloid leukemia patients [bulkRNA]

Project description:Acute myeloid leukemia is characterized by a minor fraction of primitive leukemia stem cells (LSCs) that sustain disease propagation and may be at the origin of late relapse. Yet, LSC contribution to early therapy resistance and AML regeneration remains controversial. We prospectively identified LSCs in NPM1-mutated AML patients and xenografts by means of a microRNA-126 reporter and single cell RNA sequencing, precisely discriminating LSCs from regenerating hematopoiesis, and assessed their longitudinal response to chemotherapy. We here show that chemotherapy resulted in distinct outcomes within AML subpopulations: while the bulk leukemia proliferated and differentiated with expression of oxidative-phosphorylation signatures, persisting miR-126high LSCs enforced protective stemness and dormancy features, along with a generalized inflammatory and senescence-associated response. miR-126high LSCs were enriched at diagnosis in patients with chemotherapy-refractory AML. We derived a novel miR-126high LSC transcriptional signature, which robustly stratified patients for overall survival in large AML cohorts, shining the spotlight on LSCs as determinants of early therapy resistance.

2023-02-06 | GSE185824 | GEO

Dormant leukemia stem cells reinforced by chemotherapy drive early treatment failure in acute myeloid leukemia patients [scRNA_PT]

2023-02-06 | GSE185991 | GEO

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