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Study of stem cell niche favoring drug resistance, immune suppression and maintenance of leukemia supportive microenvironment in acute myeloid leukemia

In European Journal of Immunology
By: Kode J.
Contributor(s): Nagare M | Khattry N | Sengar M | Punatar S | Gokarn A | Chiplunkar S.
Material type: materialTypeLabelArticlePublisher: 2019Description: .Subject(s): Acute Myeloid Leukemia (AML) | Mesenchymal stromal cells (MSC) | Immune-inflammatory cells In: European Journal of Immunology Vol. 49, no. S3, p. 1785.Summary: Acute Myeloid Leukemia (AML) is the most common form of leukemia in adults. Immune-inflammatory cells and mesenchymal stromal cells (MSC) which form part of tumor microenvironment, play a critical role in cancer initiation and progression. The study was aimed at profiling of leukemic blasts, immune subtypes, MSC and soluble factors in AML bone marrow microenvironment and evaluating sensitivity of leukemic blasts to chemotherapeutic drugs and immune cells. MSC were successfully cultured from bone marrow of high-risk AML patients. AML-MSC and leukemic blasts were characterized for ultrastructure by transmission electron microscopy and surface markers by flow cytometry. AML-MSC exhibited characteristic profile of MSC Type-II CD90+CD45loexpressing high percent of TLR3 than TLR4 receptors, indicating pro-tumorigenic nature. At ultrastructural level, MSC demonstrated increased mitochondria and vesicles near leading edges. MSC and leukemic blasts exhibited increased secretion of immunosuppressor adenosine and adenosine receptors A1R and A2BR, and varying expression of immune checkpoints Tim3 and PDL1. MSC were found to be resistant to anti-cancer drugs as compared to HL-60 and OCI-AML-2 cells. Laser confocal microscopy revealed increased survival of HL-60 in co-cultures due to transfer of mitochondria from MSC to leukemic blasts, suggesting transfer of cellular contents through extracellular vesicles. It was interesting to note that MSC and vesicle-rich conditioned media demonstrated significant efficacy against AML xenograft in NOD-SCID mice. Understanding crosstalk between MSC-AML blasts, and landscape of soluble factors involved in chemoresistance and immune suppression may give us leads to manipulate microenvironmental niche to control abnormal myelopoiesis in AML and develop targeted therapy.
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Articles Articles Tata Memorial Hospital
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Abstract from 17th International Congress of Immunology, 19–23 October 2019, Beijing, China

Acute Myeloid Leukemia (AML) is the most common form of leukemia in adults. Immune-inflammatory cells and mesenchymal stromal cells (MSC) which form part of tumor microenvironment, play a critical role in cancer initiation and progression. The study was aimed at profiling of leukemic blasts, immune subtypes, MSC and soluble factors in AML bone marrow microenvironment and evaluating sensitivity of leukemic blasts to chemotherapeutic drugs and immune cells. MSC were successfully cultured from bone marrow of high-risk AML patients. AML-MSC and leukemic blasts were characterized for ultrastructure by transmission electron microscopy and surface markers by flow cytometry. AML-MSC exhibited characteristic profile of MSC Type-II CD90+CD45loexpressing high percent of TLR3 than TLR4 receptors, indicating pro-tumorigenic nature. At ultrastructural level, MSC demonstrated increased mitochondria and vesicles near leading edges. MSC and leukemic blasts exhibited increased secretion of immunosuppressor adenosine and adenosine receptors A1R and A2BR, and varying expression of immune checkpoints Tim3 and PDL1. MSC were found to be resistant to anti-cancer drugs as compared to HL-60 and OCI-AML-2 cells. Laser confocal microscopy revealed increased survival of HL-60 in co-cultures due to transfer of mitochondria from MSC to leukemic blasts, suggesting transfer of cellular contents through extracellular vesicles. It was interesting to note that MSC and vesicle-rich conditioned media demonstrated significant efficacy against AML xenograft in NOD-SCID mice. Understanding crosstalk between MSC-AML blasts, and landscape of soluble factors involved in chemoresistance and immune suppression may give us leads to manipulate microenvironmental niche to control abnormal myelopoiesis in AML and develop targeted therapy.

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