Gene-expression and in vitro function of mesenchymal stromal cells are affected in juvenile myelomonocytic leukemia

Abstract

An aberrant interaction between hematopoietic stem cells and mesenchymal stromal cells has been linked to disease and shown to contribute to the pathophysiology of hematologic malignancies in murine models. Juvenile myelomonocytic leukemia is an aggressive malignant disease affecting young infants. Here we investigated the impact of juvenile myelomonocytic leukemia on mesenchymal stromal cells. Mesenchymal stromal cells were expanded from bone marrow samples of patients at diagnosis (n=9) and after hematopoietic stem cell transplantation (n=7; from 5 patients) and from healthy children (n=10). Cells were characterized by phenotyping, differentiation, gene expression analysis (of controls and samples obtained at diagnosis) and in vitro functional studies assessing immunomodulation and hematopoietic support. Mesenchymal stromal cells from patients did not differ from controls in differentiation capacity nor did they differ in their capacity to support in vitro hematopoiesis. Deep-SAGE sequencing revealed differential mRNA expression in patient-derived samples, including genes encoding proteins involved in immunomodulation and cell-cell interaction. Selected gene expression normalized during remission after successful hematopoietic stem cell transplantation. Whereas natural killer cell activation and peripheral blood mononuclear cell proliferation were not differentially affected, the suppressive effect on monocyte to dendritic cell differentiation was increased by mesenchymal stromal cells obtained at diagnosis, but not at time of remission. This study shows that active juvenile myelomonocytic leukemia affects the immune responserelated gene expression and function of mesenchymal stromal cells. In contrast, the differential gene expression of hematopoiesis-related genes could not be supported by functional data. Decreased immune surveillance might contribute to the therapy resistance and progression in juvenile myelomonocytic leukemia.

Single-cell RNA-seq identifies unique transcriptional landscapes of human nucleus pulposus and annulus fibrosus cells

“…Wnt/β-catenin signaling in the NP on the other hand progressively increased from E18.5 to 5 weeks of age 36 . Thus, the compartment-specific expression of canonical Wnt inhibitors such as SFRP1, SFRP4, DKK1, and APCDD1L [37][38][39][40] may be one of the mechanisms employed to modulate Wnt/β-catenin signaling in the AF. On the other hand, higher expression of WNT5A may suggest important roles of non-canonical Wnt signaling 41 in AF cells.…”

Catch me if you can: how AML and its niche escape immunotherapy

“…Thus, modifications of the inflammatory status induced by therapy can reshape the immunomodulatory activity of MSCs. In patients with juvenile myelomonocytic leukemia, MSCs showed differential mRNA expression, including genes involved in immunomodulation, that normalized when disease remission was achieved after HSCT [ 59 ]. If MSCs can affect immune-based therapies remains to be elucidated.…”

Mesenchymal Stem Cells in Myeloid Malignancies: A Focus on Immune Escaping and Therapeutic Implications

“…Tian et al, studied T helper subsets in AML patients and found that, while Th1, Th2, Th17, and Th22 cells and IL-22 were significantly reduced, Treg cells were increased in newly diagnosed AML patients compared to patients in remission or controls and chemotherapy ameliorated these variations [ 97 ]. MSC-mediated alteration of immune environment may be reversible with leukemia treatment, as also shown in patients with juvenile myelomonocytic leukemia, whose MSCs showed differential mRNA expression, including genes involved in immunomodulation and cell–cell interaction, that normalized during remission after successful hematopoietic stem cell transplantation [ 98 ].…”