Stromal cells downregulate miR-23a-5p to activate protective autophagy in acute myeloid leukemia

Ganesan, Saravanan; Palani, Hamenth Kumar; Lakshmanan, Vairavan; Balasundaram, Nithya; Alex, Ansu Abu; David, Sachin; Venkatraman, Arvind; Korula, Anu; George, Biju; Balasubramanian, Poonkuzhali; Palakodeti, Dasaradhi; Vyas, Neha

doi:10.1038/s41419-019-1964-8

Cited by 36 publications

(35 citation statements)

References 49 publications

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“…( Ji et al, 2009 ; Li et al, 2009 ). Consistently recent studies have provided the evidence that the BM-microenvironment transfer miRNA in leukemia cells, supporting cell survival ( Liu et al, 2015 ; Ganesan et al, 2019 ).…”

Section: Msc-derived Notch and Wnt Signaling In Leukemiasupporting

confidence: 69%

The Role of Notch and Wnt Signaling in MSC Communication in Normal and Leukemic Bone Marrow Niche

Kamga

Bazzoni

Collo

et al. 2021

Front. Cell Dev. Biol.

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Notch and Wnt signaling are highly conserved intercellular communication pathways involved in developmental processes, such as hematopoiesis. Even though data from literature support a role for these two pathways in both physiological hematopoiesis and leukemia, there are still many controversies concerning the nature of their contribution. Early studies, strengthened by findings from T-cell acute lymphoblastic leukemia (T-ALL), have focused their investigation on the mutations in genes encoding for components of the pathways, with limited results except for B-cell chronic lymphocytic leukemia (CLL); in because in other leukemia the two pathways could be hyper-expressed without genetic abnormalities. As normal and malignant hematopoiesis require close and complex interactions between hematopoietic cells and specialized bone marrow (BM) niche cells, recent studies have focused on the role of Notch and Wnt signaling in the context of normal crosstalk between hematopoietic/leukemia cells and stromal components. Amongst the latter, mesenchymal stromal/stem cells (MSCs) play a pivotal role as multipotent non-hematopoietic cells capable of giving rise to most of the BM niche stromal cells, including fibroblasts, adipocytes, and osteocytes. Indeed, MSCs express and secrete a broad pattern of bioactive molecules, including Notch and Wnt molecules, that support all the phases of the hematopoiesis, including self-renewal, proliferation and differentiation. Herein, we provide an overview on recent advances on the contribution of MSC-derived Notch and Wnt signaling to hematopoiesis and leukemia development.

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Section: Msc-derived Notch and Wnt Signaling In Leukemiasupporting

confidence: 69%

The Role of Notch and Wnt Signaling in MSC Communication in Normal and Leukemic Bone Marrow Niche

Kamga

Bazzoni

Collo

et al. 2021

Front. Cell Dev. Biol.

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“…Stromal cell-induced NF-kB signaling in leukemic cells downregulates miR-23-5p, which causes upregulation of protective autophagy via TLR2. Thus, leukemic cells are protected from chemotherapy-induced apoptosis [ 156 ]. Furthermore, it has been shown that doxorubicin treatment induced miR-21-5p expression in mesenchymal stem cells and derived exosomes.…”

Section: Combination With Cancer Therapy To Counteract Mir-mediatementioning

confidence: 99%

Therapeutic Targeting of MicroRNAs in the Tumor Microenvironment

Raue

Frank

Syed

et al. 2021

IJMS

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The tumor-microenvironment (TME) is an amalgamation of various factors derived from malignant cells and infiltrating host cells, including cells of the immune system. One of the important factors of the TME is microRNAs (miRs) that regulate target gene expression at a post transcriptional level. MiRs have been found to be dysregulated in tumor as well as in stromal cells and they emerged as important regulators of tumorigenesis. In fact, miRs regulate almost all hallmarks of cancer, thus making them attractive tools and targets for novel anti-tumoral treatment strategies. Tumor to stroma cell cross-propagation of miRs to regulate protumoral functions has been a salient feature of the TME. MiRs can either act as tumor suppressors or oncogenes (oncomiRs) and both miR mimics as well as miR inhibitors (antimiRs) have been used in preclinical trials to alter cancer and stromal cell phenotypes. Owing to their cascading ability to regulate upstream target genes and their chemical nature, which allows specific pharmacological targeting, miRs are attractive targets for anti-tumor therapy. In this review, we cover a recent update on our understanding of dysregulated miRs in the TME and provide an overview of how these miRs are involved in current cancer-therapeutic approaches from bench to bedside.

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“…Immunofluorescence: This was done as previously reported by us (13). In summary, the myeloma cells were treated with drugs for 24 hours and cytospin slides were made.…”

Section: Co-immunoprecipitation and Immunoblots: Myeloma Cells Lines mentioning

confidence: 99%

Combination Lenalidomide/Bortezomib Treatment Synergistically Induces Calpain-Dependent Ikaros Cleavage and Apoptosis in Myeloma Cells

Ganesan

Palani

Balasundaram

et al. 2020

Molecular Cancer Research

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Multiple myeloma had been successfully treated by combining lenalidomide and bortezomib with reports suggesting benefits of such a combination even in relapsed/refractory cases. Recently, it was demonstrated that Ikaros degradation by lenalidomide happens via proteasome-dependent pathway and this process is critical for the eradication of myeloma cells. On the basis of this, an antagonistic effect should be observed if a combination of both these agents were used, which however is not the observation seen in the clinical setting. Our study demonstrates that when these agents are combined they exhibit a synergistic activity against myeloma cells and degradation of Ikaros happens by a proteasome-independent calcium-induced calpain pathway. Our study identifies the crucial role of calcium-induced calpain pathway in inducing apoptosis of myeloma cells when this combination or lenalidomide and bortezomib is used. We also report that this combination enhanced the expression of CD38 compared with lenalidomide alone. Thus, data from our study would establish the rationale for the addition of daratumumab along with this combination to further enhance therapeutic activity against multiple myeloma. Implications: Lenalidomide and bortezomib combination degrades IKZF1 in multiple myeloma through a calcium-dependent calpain and caspase pathway. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/18/4/529/F1.large.jpg.

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Stromal cells downregulate miR-23a-5p to activate protective autophagy in acute myeloid leukemia

Cited by 36 publications

References 49 publications

The Role of Notch and Wnt Signaling in MSC Communication in Normal and Leukemic Bone Marrow Niche

The Role of Notch and Wnt Signaling in MSC Communication in Normal and Leukemic Bone Marrow Niche

Therapeutic Targeting of MicroRNAs in the Tumor Microenvironment

Combination Lenalidomide/Bortezomib Treatment Synergistically Induces Calpain-Dependent Ikaros Cleavage and Apoptosis in Myeloma Cells

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