MRAN expression profiles in bone marrow mesenchymal stem cells (MSC) from Wild Type and Lama4-deficient mice co-cultured with MLL-AF9 AML cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE185846 | GEO | 2022/02/16
REPOSITORIES: GEO
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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.
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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.
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Project description:Our CRISPR-based pharmacogenomic screening identified the E3 ubiquitin ligase Herc1 as a key modulator of sensitivity to cytarabine (Ara-C) chemotherapy in the MLL/AF9 (MA) mouse AML model both in vitro and in vivo. To identify the intracellular proteins whose abundance is modulated by Herc1, we performed comparative LC-MS3 analysis of in vitro-cultured MA mouse AML cells that were transduced with either a small-guide RNA targeting Herc1 (i.e., CRISPR-mediated Herc1-knockout) or a control non-targeting small-guide RNA, at steady state or after brief exposure to Ara-C (200 nMol for 6 hours).
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Project description:While extensive efforts have been on understanding bone marrow (BM) niche contribution to normal and malignant hematopoiesis, the role of extramedullary niches has been largely ignored. Evidence suggests a BM mesenchymal stem cell (MSC) counterpart exists in skin. However, their native identity and role in hematopoiesis remain unexplored. Here, we demonstrated that mouse skin harbors MSC subsets that are phenotypically and molecularly similar to BM MSCs, including a primitive MSC population marked by Early B-cell Factor 2 (Ebf2) and downstream MSCs lacking Ebf2. Functionally, skin MSCs not only support acute myeloid leukemia (AML) stem cells but also protect them from chemotherapy. This persistence of AML cells in skin were further amplified in AML-promoting microenvironment lacking Lama4. Our study demonstrated the features of extramedullary niches in skin and their previously unrecognized role in supporting AML stem cells during chemotherapy, opening a new path for understanding the extramedullary manifestation of AML in patients.
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Project description:mRAN expression profiles in bone marrow mesenchymal stem cells (MSC) from Wild Type and Lama4-deficient mice co-cultured with MLL-AF9 AML cells
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