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CD200 expression marks leukemia stem cell (LSC) in human AML part 3

ABSTRACT: The leukemia stem cell (LSC) populations of acute myeloid leukemia (AML) exhibit phenotypic, genetic and functional heterogeneity that contribute to therapy failure and relapse. Progress towards understanding the mechanistic basis for therapy resistance in LSCs has been hampered by difficulties in isolating cell fractions that enrich for the entire heterogeneous population of LSCs within individual AML samples. We previously reported that CD200 gene expression is upregulated in LSC-containing AML fractions. We demonstrate that CD200 is present on a greater proportion of CD45dim blasts compared to more differentiated CD45high cells in AML patient samples. In 75% of AML cases examined, CD200 was expressed on 10% of CD45dim blasts; of these, CD200 identified LSCs within the blast population in 90% of samples tested in xenotransplantation assays. Notably, CD200 expression captured both CD34- and CD34- LSCs within individual AML samples. Highly purified CD45dimCD200+ LSC-containing blasts were enriched in primitive HSC/progenitor-like signatures, while CD45dimCD200- nonengrafting blasts were enriched in myeloid-like signature. Moreover, analysis of CD45dimCD200+ blasts from NPM1-mutated AMLs also demonstrated an enrichment of primitive gene expression signatures compared to unfractionated (bulk) cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159322 | GEO | 2020/10/10

REPOSITORIES: GEO

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CD200 expression marks leukemia stem cells (LSC) in human AML part 2

Project description:The leukemia stem cell (LSC) populations of acute myeloid leukemia (AML) exhibit phenotypic, genetic and functional heterogeneity that contribute to therapy failure and relapse. Progress towards understanding the mechanistic basis for therapy resistance in LSCs has been hampered by difficulties in isolating cell fractions that enrich for the entire heterogeneous population of LSCs within individual AML samples. We previously reported that CD200 gene expression is upregulated in LSC-containing AML fractions. We demonstrate that CD200 is present on a greater proportion of CD45dim blasts compared to more differentiated CD45high cells in AML patient samples. In 75% of AML cases examined, CD200 was expressed on 10% of CD45dim blasts; of these, CD200 identified LSCs within the blast population in 90% of samples tested in xenotransplantation assays. Notably, CD200 expression captured both CD34- and CD34- LSCs within individual AML samples. Highly purified CD45dimCD200+ LSC-containing blasts were enriched in primitive HSC/progenitor-like signatures, while CD45dimCD200- nonengrafting blasts were enriched in myeloid-like signature. Moreover, analysis of CD45dimCD200+ blasts from NPM1-mutated AMLs also demonstrated an enrichment of primitive gene expression signatures compared to unfractionated (bulk) cells.

2020-10-10 | GSE159321 | GEO

CD200 expression marks leukemia stem cell (LSC) in human AML part 1

2020-10-10 | GSE159319 | GEO

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

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

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 | GSE185834 | GEO

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

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

CD38-directed, single-chain T cell-engager targets leukemia stem cells through IFNγ-induced CD38 expression [scRNAseq]

Project description:Treatment resistance of leukemia stem cells (LSCs) and suppression of the autologous immune system represent major challenges to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38pos), LSCs are frequently enriched in the CD34posCD38neg blast fraction. Here, we report that IFNγ reduces LSCs clonogenic activity and induces CD38 upregulation in both CD38pos and CD38neg LSC-enriched blasts. IFNγ-induced CD38 upregulation depends on IRF-1 transcriptional activation of the CD38 promoter. To leverage this observation, we created a novel compact, single-chain CD38-CD3 T cell engager (BN-CD38) designed to promote an effective immunological synapse between both CD8 and CD4 T cells and CD38pos AML cells. We demonstrate that BN-CD38 engages autologous CD4pos and CD8pos T cells and CD38pos AML blasts leading to T cell activation and expansion and to the elimination of leukemia cells in an autologous setting. Importantly, BN-CD38 engagement induces the release of high levels of IFNγ, driving the expression of CD38 on CD34posCD38neg LSC-enriched blasts and their subsequent elimination. Critically, while BN-CD38 showed significant in vivo efficacy across multiple disseminated AML cell lines and patient derived xenograft models, it did not affect normal hematopoietic stem cell clonogenicity and the development of multi-lineage human immune cells in CD34pos humanized mice. Taken together, this study provides important insights to target and eliminate AML LSCs.

2024-01-27 | GSE253921 | GEO

CD38-directed, single-chain T cell-engager targets leukemia stem cells through IFNγ-induced CD38 expression [bulkRNAseq]

2024-01-27 | GSE253920 | GEO

Microarray data of human MLLr AML cells with or without CD93 expression

Project description:Leukemia stem cells (LSCs) share several crucial properties with hematopoietic stem cells (HSCs) including self-renewal, cell cycle quiescence, and expression of a CD34+CD38- immunophenotype, which complicates efforts to eradicate AML by therapeutically targeting LSCs without adversely affecting HSCs. Here we report that CD93, a C-type lectin transmembrane receptor, is preferentially expressed on the cell surface of LSCs compared with HSCs in the genetic subtype of AML with genomic rearrangements of the MLL gene. LSCs that selectively express CD93 are actively cycling, and highly enriched for xeno-engraftment potential, yet comprise a minor component of an otherwise quiescent CD34+CD38- compartment of human AML. Notably, CD93 is required for LSC function in MLL leukemogenesis, and is not simply a passive surface marker co-expressed on LSCs. Thus, CD93 selectively marks and essentially maintains LSCs, and identifies them as predominantly cycling, non-quiescent leukemia-initiating cells in MLL-rearranged AML.

2015-10-02 | GSE64776 | GEO

Differential gene expression in leukemic blasts and leukemic stem cells (LSC) sorted from pediatric AML patients compared to control myeloblasts and hematopoietic stem cells (HSC) sorted from cord blood

Project description:Purpose: Currently, only few reports address the molecular abnormalities of LSC compared to HSC in pedAML. Identifying LSC aberrations is crucial to tackle the high relapse rate and to develop therapeutic targeting strategies for LSC elimination, while ensuring salvage of normal HSCs. Methods: Blasts and stem cells were separated based on CD38 expression (positive and negative, respectively). Leukemic blasts (n=4), LSCs (n=3) and lymphocytes (n=4) were sorted from 4 de novo pedAML patients (two FLT3-ITD, two FLT3 WT). As control, CD34+CD38+ (n=3) and CD34+CD38- (n=2) cells were sorted from cord blood (CB). RNA was extracted using the miRNeasy Mini Kit (Qiagen) in combination with on-column DNase I digestion (RNase-Free DNase set, Qiagen). Mean RIN of all sorted fractions was 9.3 (95% CI 9.1-9.5). All sorted cell fractions (n=15) were profiled on a custom 8x60K human Gene expression micro-array, containing probes for all human protein-coding genes with lncRNA content based on LNCipedia 2.13 (Biogazelle), as follows: 20 ng RNA was pre-amplified using the Complete Whole Transcriptome Amplification Kit (Sigma-Aldrich). Amplified RNA was subsequently labelled using the Genomic DNA ULS Labeling Kit (Agilent) and hybridized to the array in combination with CGH blocking to reduce background signaling. Micro-arrays were analyzed using an Agilent micro-array scanner and Feature Extraction software (v12.0). Probe intensities were background subtracted, quantile-normalised and log2-based probe intensities were calculated.

2022-03-09 | GSE128103 | GEO

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