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Wnt Pathway Contributes to the Protection of Acute Lymphoblastic Leukemia Cells by Bone Marrow Stromal Cells and May Be a Therapeutic Target

ABSTRACT: Acute lymphoblastic leukemia (ALL) is the most common cancer in children and one of the most common cancers in adults. Although most children with ALL can be cured, approximately 60% of adults with ALL develop drug resistance or experience relapse and cannot be cured with traditional chemotherapy. One possible reason that treatment fails to eradicate ALL cells is that residual leukemia cells are protected by various components of the bone marrow microenvironment, such as marrow stromal cells (MSCs). To evaluate the effects of MSCs on ALL cell survival and response to chemotherapy, we co-cultured ALL cells with human or murine MSCs. We found that both human and murine MSCs protected human ALL cell lines and primary ALL cells from spontaneous and Ara-C-induced apoptosis. MSCs also modulated the cell cycle and increased ALL cell proliferation. Specifically, we found that Wnt signaling activation contributed to MSC-mediated drug resistance. In contrast, blocking the Wnt pathway led to decreased ALL cell viability. Chemotherapy plus the β-catenin inhibitor XAV939 resulted in a decreased tumor burden and improved overall survival in an ALL mouse model compared with chemotherapy alone. Our data demonstrate that targeting the Wnt pathway may represent an innovative approach to the treatment of ALL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE36372 | GEO | 2014/01/01

SECONDARY ACCESSION(S): PRJNA153247

REPOSITORIES: GEO

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Wnt Pathway Contributes to the Protection of Acute Lymphoblastic Leukemia Cells by Bone Marrow Stromal Cells and May Be a Therapeutic Target

Project description:Acute lymphoblastic leukemia (ALL) is the most common cancer in children and one of the most common cancers in adults. Although most children with ALL can be cured, approximately 60% of adults with ALL develop drug resistance or experience relapse and cannot be cured with traditional chemotherapy. One possible reason that treatment fails to eradicate ALL cells is that residual leukemia cells are protected by various components of the bone marrow microenvironment, such as marrow stromal cells (MSCs). To evaluate the effects of MSCs on ALL cell survival and response to chemotherapy, we co-cultured ALL cells with human or murine MSCs. We found that both human and murine MSCs protected human ALL cell lines and primary ALL cells from spontaneous and Ara-C-induced apoptosis. MSCs also modulated the cell cycle and increased ALL cell proliferation. Specifically, we found that Wnt signaling activation contributed to MSC-mediated drug resistance. In contrast, blocking the Wnt pathway led to decreased ALL cell viability. Chemotherapy plus the β-catenin inhibitor XAV939 resulted in a decreased tumor burden and improved overall survival in an ALL mouse model compared with chemotherapy alone. Our data demonstrate that targeting the Wnt pathway may represent an innovative approach to the treatment of ALL. Reh cells were harvested after being treated with Ara-C for 48 hours, with or without HS and HS-5 human stromal cells. Independent triplicate samples were used in the experiments. Total RNA was prepared using TRI reagent (Ambion, Austin, TX) and amplification and synthesis of cRNA was performed using Illumina TotalPrep RNA amplification kit (Ambion). cRNA was then hybridized to the HumanHT-12 v3 Expression BeadChip (Illumina, San Diego, CA) according to the manufacturer's instructions.

2014-01-01 | E-GEOD-36372 | biostudies-arrayexpress

Expression data of mesenchymal stromal cells after 40 hours of co-culture with primary B-cell precursor acute lymphoblastic leukemia cells

Project description:B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells reside in the bone marrow microenvironment, where they are protected against chemotherapeutic agents. Mesenchymal stromal cells (MSCs) are key components of this supporting framework. The present study aimed to unravel whether MSCs derived from pediatric BCP-ALL patients (leukemic MSCs) differ from MSCs derived from healthy pediatric donors (control-MSCs). Therefore, we studied their gene expression profiles after 40 hours of co-culture with primary B-cell precursor acute lymphoblastic leukemia cells. MSCs were sorted using fluorescence-activated cell sorting (FACS).

2020-07-13 | GSE101454 | GEO

Expression data from mesenchymal stromal cells derived from pediatric leukemia patients and healthy pediatric controls

2020-07-13 | GSE101425 | GEO

Transcription profiling of human ALL exhibiting cross-resistance to prednisolone, vincristine, asparaginase and daunorubicinchemotherapy cross-resistance and treatment response in childhood acute lymphoblastic leukemia

Project description:Acute lymphoblastic leukemia (ALL) can be cured with combination chemotherapy in over 75% of children, but the cause of treatment failure in the remaining patients is unknown. We determined the sensitivity of ALL cells to individual antileukemic agents in 441 patients, and used a genome-wide approach to identify 45 genes differentially expressed in ALL exhibiting cross-resistance to prednisolone, vincristine, asparaginase and daunorubicin. We also identified a distinct phenotype of discordant resistance to asparaginase and vincristine and 139 genes whose expression was associated with this novel phenotype. The expression of these genes discriminated treatment outcome in two independent patient populations, identifying a subset of patients with a markedly inferior outcome (37%Â±13% 5-year DFS).

2008-06-12 | E-GEOD-2351 | biostudies-arrayexpress

The role of mesenchymal stromal cells (MSC) in the development of acute myeloid leukemia

Project description:Acute myeloid leukemia (AML) is a clonal disorder of hematopoietic stem cells with a poor prognosis. It has been reported in many tumors that mesenchymal stem/ stromal cells (MSCs) support the growth of the malignant cells. In this study we analyzed the interaction between MSCs and AML cells in patients and in murine models of human AML. We found that MSCs from AML patients or leukemic mice supported the growth of AML cells in vitro better than MSCs originating from healthy mice or control persons. Interestingly, MSCs from AML patients who achieved complete remission didn’t support the growth of leukemia cells in vitro anymore. Due to the difficulty to obtain sufficient human MSCs, we developed a novel method to immortalize human MSCs. Immortalized MSC cells derived from AML patients also supported the growth of human AML cells better than MSC cells derived from a healthy donor. Among others, AMSCs increased entering of leukemic cells into cell cycle and at the same time protected the leukemia cells against exogenous toxic events such as chemotherapy or irradiation. In vivo, we observed an increase in the number of MSCs in the bone marrow of leukemic mice compared to healthy mice. Microarray data of AMSCs show upregulation of epithelial mesenchymal trasition genes. The polarization of MSCs towards an AML-supporting state depends on upregulated expression of the transcription factor Growth factor independence 1 (Gfi1). Loss of Gfi1 abrogated the tumor-supporting state of AML-associated MSCs. In summary, we report that MSCs support the growth of AML cells in a Gfi1-dependent manner.

2020-08-22 | GSE102928 | GEO

chemotherapy cross-resistance and treatment response in childhood acute lymphoblastic leukemia

2005-04-01 | GSE2351 | GEO

Role of Hopx in myogenesis and commitment [HopxKO+Wnt]

Project description:Progenitor cells require coordinated expression of lineage-specific genes to regulate differentiation into daughter cell types. Hopx labels cardiac progenitors that are commited to the cardiac myocyte lineage. Hopx-deficiency leads to thin myocardium in approximately mid-gestation lethality in approximately 50% of embryos (secondary to thin myocardium and presumed cardiac rupture). Hopx-/- EBs display impaired myogenesis during cardiac differentiation. ChIP-seq and RNA expression analysis suggests that Hopx down regulates Wnt signaling by directly occupying and repressing wnt ligand genes. Analysis of embryoid bodies on day 8 of cardiac differentiation. RNA was made of from Hopx +/- embryoid bodies or Hopx -/- embryoid bodies treated with 12.5 uM XAV939. Heterozygous embryoid bodies included 0 uM XAV939, a well-characterized, known Wnt inhibitor. Embryonic stem cell lines were derived from littermate mouse blastocysts. Results provide insight into gene programs regulated by Hopx in cardiac development.

2015-06-01 | GSE67252 | 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

mRAN expression profiles in bone marrow mesenchymal stem cells (MSC) from Wild Type and Lama4-deficient mice co-cultured with MLL-AF9 AML cells

Project description:Bone marrow (BM) niche contributes to hematopoietic regeneration and can be remodeled by leukemic cells. We have found that Lama4 deletion in mouse mesenchymal stem cells (MSCs) could promote the proliferation of MLL-AF9 acute myeloid leukemia (AML) cells and chemoresistance of the cells to chemotherapy cytarabine. However, whether Lama4 deficient MSCs are more susseptible for AML cell remodeling remains to be explored. Here we report that differential molecular alterations in Lama4 deficient MSCs compared to wild type MSCs after being exposed to the AML cells for 48hours, which might be related to the enhanced AML cell proliferation and chemoresistance.

2022-02-16 | GSE185846 | GEO

Characterization of mesenchymal stem cells in pre-B acute lymphoblastic leukemia

Project description:The way in which leukemia develops, progresses and responds to treatment is mediated largely by components of the bone marrow microenvironment (BMM). Increasing evidence shows that leukemic cells hijack the BMM, altering its functioning and establishing leukemia-supportive interactions with stromal and immune cells. While previous work has highlighted functional defects in the mesenchymal stem cell (MSC) population from the BMM of acute leukemias, a thorough characterization and molecular profiling of MSCs of pre-B cell acute lymphoblastic leukemia (B-ALL), the most common cancer in children, has not been conducted. Here, we investigated the transcriptome profiles of MSCs isolated from the BMM of an immunocompetent BCR-ABL1+ model of B-ALL.

2023-01-31 | GSE208719 | GEO

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