Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Leukemia-on-a-Chip: Dissecting the chemo-resistance mechanisms in B-cell acute lymphoblastic leukemia (B-ALL) bone marrow niche

ABSTRACT: B-cell acute lymphoblastic leukemia (B-ALL) blasts hijack the bone marrow (BM) microenvironment to form chemo-protective leukemic BM ‘niches’, facilitating chemo-resistance and, ultimately, disease relapse. However, the ability to dissect these evolving, complex interactions among distinct B-ALL subtypes and their varying BM niches is limited with current in vivo methods. Herein, we reconstituted an in vitro three-dimensional (3D) organotypic leukemic BM niche model using a ‘Leukemia-on-a-Chip’ platform and comparatively studied the spatial and genetic heterogeneity of the BM niche in regulating B-ALL chemotherapy resistance. By emulating the leukemia BM anatomy in vitro, we determined that the perivascular and endosteal niches, through providing cytokine (e.g. CXCL12) and adhesive (e.g. VCAM-1/OPN) signals, differentially enhance downstream leukemia-intrinsic NF-κB signaling to support B-ALL survival and regulate cell cycle-related signaling to promote dormancy, which following demonstrated the pre-clinical utility of this microphysiological system to screen concomitant niche-directed therapies. Furthermore, we revealed the heterogeneity across different B-ALL subtypes by mapping subtype-specific leukemia and niche signals with application of single-cell RNA sequencing and analysis, which may contribute to chemotherapy resistance and disease relapse. Together, these results validate that our Leukemia-on-a-Chip allows for real-time and controllable dissection of the dynamic and heterotypic interactions between leukemia blasts and their BM microenvironment, which may translate to personalized therapeutics screening and disease management.

ORGANISM(S): Homo sapiens

PROVIDER: GSE138811 | GEO | 2020/10/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Blast cells surviving acute myeloid leukemia induction therapy are in cycle with a signature of FOXM1 activity

Project description:Disease relapse remains common following treatment of acute myeloid leukemia (AML) and is due to chemoresistance of leukemia cells with disease repopulating potential. To date, attempts to define the characteristics of in vivo resistant blasts have focused on comparisons between leukemic cells at presentation and relapse. However, further treatment responses are often seen following relapse, suggesting that most blasts remain chemosensitive. Here we characterize in vivo chemoresistant blasts by studying the transcriptional and genetic features of blasts from before and after induction chemotherapy using paired samples from 6 patients with primary refractory AML.

2021-10-04 | GSE162542 | GEO

leukemia propagating cells rebuild an evolving niche in response to therapy

Project description:Residence of cancer-propagating cells (CPCs) within preferential microenvironmental niches has a major part in evading therapy. However, the nature of niches involved and the mechanisms protecting CPCs remain largely unknown. We addressed these issues in mouse transplantation models of acute lymphoblastic leukemia (ALL). When the engrafted leukemic cells substantially damaged adjacent vascular structures and endosteal linings in the bone marrow (BM), after chemotherapy small foci of CPCs were retained, surrounded by sheaths of supporting cells that comprise a novel niche. We investigated patients’ BM biopsies and found evidence of a similar process in patients receiving induction-therapy. The efficacy of chemotherapy was enhanced by interfering with the niche formation or niche-CPC interaction. We therefore identified a therapy-induced niche that protects CPCs. We used microarrays to compare the gene expression profile of ALL cell line (Nalm-6) from model (A0D) mice and rediduel cells from Ara-C treatment for 2 days (A2D) mice.

2014-04-21 | GSE56273 | GEO

leukemia propagating cells rebuild an evolving niche in response to therapy

2014-04-21 | E-GEOD-56273 | biostudies-arrayexpress

Expression data from human AML blasts and healthy CD34+ bone marrow cells

Project description:Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk between AML cells and the bone marrow (BM) stroma is a major mechanism underlying therapy resistance in AML. Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma. Whether IMiDs may improve the efficacy of current standard treatment in AML remains understudied. Here, we have exploited in vitro and in vivo preclinical AML models to analyze whether IMiDs potentiate the efficacy of AraC/Iradubicin (standard AML chemotherapy) by interfering with the BM stroma-mediated chemoresistance. We report that lenalidomide and pomalidomide have cytotoxic effects on neither AML cells nor BM-MSCs, but they increase the immunosuppressive/immunomodulatory properties of BM-MSCs. When combined with AraC and Idarubicin, IMiDs fail to circumvent BM stroma-mediated resistance of AML cells in vitro and in vivo but induce robust extramedullary mobilization of AML cells. When administered as a single agent, lenalidomide highly mobilizes AML cells, but not healthy CD34+ cells, to peripheral blood (PB) likely through specific downregulation of CXCR4 in AML blasts. Global gene expression profiling supports a migratory/mobilization gene signature in lenalidomide-treated AML blasts but not in CD34+ cells. Collectively, IMiDs mobilize AML blasts to PB through downregulation of CXCR4 but do not improve AraC/Idarubicin activity in a preclinical model of AML.

2019-05-17 | GSE106748 | GEO

Cell-Cycle Restriction Sustains Therapy-Resistant Pre-Leukemic Stem Cells

Project description:Pre-leukemic stem cells (pre-LSCs) provide a reservoir of cells that evolve to acute leukemia and cause relapse following chemotherapy. We postulated that quiescence of pre-LSCs is an important mechanism of therapeutic resistance. Using a doxycycline-inducible H2B-GFP transgene in a mouse model of T-cell acute lymphoblastic leukemia, we show that long-term self-renewal, clonal evolution and resistance to chemo-radiation are intrinsically linked to restricted cell cycle. We show that restricted cell cycle of pre-LSCs requires the presence of the CDK inhibitor p21, with absence of p21 leading to chemosensitivity and clonal extinction by loss of asymmetric cell division and terminal differentiation. These results provide a model to identify and test strategies to eradicate an important source of clonal evolution and leukemic relapse.

2018-12-21 | GSE110132 | GEO

Targeting mesenchymal stromal cells plasticity to reroute acute myeloid leukemia course

Project description:MSC and AML dual targeting to treat pediatric AML Bone marrow (BM) microenvironment supports the regulation of normal hematopoiesis through a finely tuned balance of self-renewal and differentiation processes, cell-cell interaction and secretion of cytokines that during leukemogenesis are severely compromised and favor tumor cell growth. In pediatric acute myeloid leukemia (AML), chemotherapy is the standard of care, but still >30% of patients relapse. The need to accelerate the evaluation of innovative medicines prompted us to investigate the mesenchymal stromal cell (MSCs) role in the leukemic niche to define its contribution to the mechanisms of leukemia escape. We generated humanized three-dimensional (3D) niche with AML cells and MSCs derived from patients (AML-MSCs) or healthy donors. We observed that AML cells establish physical connections with MSCs, mediating a reprogrammed transcriptome inducing aberrant cell proliferation and differentiation, and severely compromising their immunomodulatory capability. We confirmed AML cells endow h-MSCs with a pro-oncogenic transcriptional profile and functions similar to the AML-MSCs when co-cultured in vitro. Conversely, MSCs derived from BM of patients at time of disease remission showed recovered healthy features, at transcriptional and functional levels, including the secretome. We sustained AML blasts altering MSC cell activities in the BM niche in order to favor disease development and progression, becoming a pharmacological target. We discovered that a novel AML-MSCs selective CaV1.2 channel blocker drug, Lercanidipine, is able to impair leukemia progression in 3D both, in vitro and when implanted in vivo, if used in combination with chemotherapy, supporting the hypothesis that synergistic effects can be obtained by dual targeting approaches.

2021-07-01 | GSE169428 | GEO

CKS1-dependent proteostatic regulation has dual roles in combating acute myeloid leukemia whilst protecting normal hematopoiesis

Project description:Acute myeloid leukemia (AML) is an aggressive hematological disorder comprised of a hierarchy of quiescent leukemic stem cells and fast proliferating blasts with limited self-renewal ability. Significant plasticity in the AML epigenome and metabolome results in a high rate of drug resistance and relapse, with extremely low 2-year survival rates in the poorest cytogenetic risk patients. The current backbone of clinical induction chemotherapy reduces total disease burden, but does not deplete leukemic stem cells which reconstitute the disease in vivo, and also suffers from severe toxicity of healthy hematopoietic cells. Whilst much work has been done to identify epigenetic vulnerabilities in AML, little is known about protein dynamics, and here we explored the therapeutic inhibition of highly specific CKS1-dependent protein degradation. We report a dual role for CKS1-depdent protein degradation in specifically targeting AML, whilst protecting normal hematopoietic cells from chemotherapeutic toxicity.

2022-07-20 | PXD022754 | Pride

Combined Functional and Genomic Single clonal Stem Cell Analysis Pinpointed at Diagnosis Leukemic Clones Responsible for Acute Myeloid Leukemia Relapse

Project description:Acute myeloid leukemia (AML) is a hematological malignancy, associated with unfavorable patient outcome primarily due to disease relapse. Since specific early leukemic hematopoietic stem and progenitor cells (HSPCs) are suggested to be responsible for AML propagation, the present study used single cell analysis (SCA) to detect and explore rare relapse-initiating HSPC clones, appearing already at diagnosis. To address inherent SCA limitations, we developed a unique high-resolution technique capable to follow single cell-derived subclones of heterogeneous HSPC subpopulations during AML evolution. Each of these subclones was evaluated for chemo-resistance, in-vivo leukemogenic potential, mutational profile, and the subclone cell of origin identified using reconstruction of phylogenetic trees. This study, employing combined functional and genomic analyses, unraveled the patient-specific HSPC subpopulations involved in chemo-resistance and determined, at time of diagnosis, the phenotype of the relapse-initiating clone, allowing early prediction of AML recurrence and suggesting novel precise therapeutic targets for relapse prevention.

2022-11-12 | E-MTAB-12238 | biostudies-arrayexpress

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

mRAN expression profiles in mesenchymal progenitor cells freshly-sorted from Wild Type and Lama4-deficient mice

Project description:Bone marrow (BM) niche contributes to hematopoietic regeneration under stress like irradiation and leukemia. However, the mechanisms remain poorly defined. We here report that Lama4 deletion in mice results in reduction of mesenchymal progenitors (MPCs) and endothelial cells in BM. Following irradiation, Lama4-/- mice displayed impaired hematopoiesis recovery accompanied with dysregulation of BM niche factors like angiopoietin-1 and Tgfb1 in the MPCs. Post-transplantation of MLL-AF9 acute myeloid leukemia (AML) cells, we observed accelerated AML onset in Lama4-/- mice. Moreover, these Lama4-/- AML mice displayed faster relapse after therapeutic BM transplantation. Mechanistically, Lama4-/- niche promoted AML cell proliferation and chemoresistance to chemotherapy cytarabine by conferring AML greater antioxidant activity. Together, our study demonstrates that Lama4 is required to maintain hematopoietic niche integrity and to suppress AML progression and chemoresistance by restricting metabolic defense support to AML. Therefore, activating Lama4 signaling pathways may offer potential new therapeutic options for AML.

2022-02-16 | GSE167404 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data