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Orsel, J.

Publications and source records attributed to Orsel, J..

2 recordsLinked to original sources
bioRxiv2023

Various Cell Types in the Bone Marrow sustain Primary B-Cell Precursor Acute Lymphoblastic Leukemia

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) originates from the bone marrow, which besides hematopoietic cells also contains different (supportive) cell types, including mesenchymal stromal cells (MSCs), osteocytes, chondrocytes, fibroblasts, and adipocytes. These (supportive) cell types create a bone marrow microenvironment that facilitates leukemogenesis and provide a survival benefit to leukemic cells that also affects the response to chemotherapeutic drugs. We here show that the survival benefit provided by supportive tissues does not depend on the type of supportive cells and does not differ between supportive cells collected at the time of full leukemia (diagnosis), at end of consolidation therapy or from healthy controls. The need for supportive cells, however, clearly differed between subtypes of BCP-ALL, with BCR-ABL1-positive and TCF3-PBX1-positive subtypes being the most dependent on this support. Various supportive cell types provided a survival benefit to BCP-ALL cells, with a median benefit of 18% (chondrocytes) and 30-36% (MSCs, osteocytes, and fibroblasts), which was not observed for mature adipocytes. This benefit was direct cell-cell contact dependent and decreased upon physical separation of cell populations in a transwell setting. BCP-ALL cells in contrast to MSCs and the other supportive tissue types hardly produce cyto-/chemokines. The secretome of MSCs changed upon co-culture with BCP-ALL cells resulting in 1.2-fold to 1.4-fold (median) higher levels for the cyto-/chemokines IL6, CCL22, CXCL10, and CXCL5. Together, these data suggest that BCP-ALL cells manipulate different components of the bone marrow supportive tissues via direct cell-cell contact which favors the survival of leukemic cells. This strengthens our earlier observation that BCP-ALL cells hijack the bone marrow microenvironment and offers the perspective that interference with this stromal interaction and/or released cyto-/chemokines may be of additive value in the treatment of BCP-ALL.

cancer biology↗
bioRxiv2023

B-Cell Precursor Acute Lymphoblastic Leukemia elicits an Interferon-α/β response in Bone Marrow-derived Mesenchymal Stroma.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can hijack the normal bone marrow microenvironment to create a leukemic niche which facilitates blast cell survival and promotes drug resistance. Bone marrow-derived mesenchymal stromal cells (MSCs) mimic this protective environment in ex vivo co-cultures with leukemic cells obtained from children with newly diagnosed BCP-ALL. We examined the potential mechanisms of this protection by RNA sequencing of flow-sorted MSCs after co-culture with BCP-ALL cells. Leukemic cells induced an interferon (IFN)-related gene signature in MSCs, which was partially dependent on cell-cell signaling by tunneling nanotubes. The signature was selectively induced by BCP-ALL cells, most profoundly by ETV6-RUNX1 positive ALL cells, as co-culture of MSCs with healthy immune cells did not provoke a similar IFN signature. Leukemic cells and MSCs both secreted IFN and IFN{beta}, but no IFN{gamma}. In line, the IFN-gene signature was sensitive to blockade of IFN/{beta} signaling, but less to that of IFN{gamma}. The viability of leukemic cells and level of resistance to three chemotherapeutic agents was not affected by interference with IFN signaling using selective IFN/{beta} inhibitors or silencing of IFN-related genes. Taken together, our data suggest that the leukemia-induced expression of IFN/{beta}-related genes by MSCs does not support survival of BCP-ALL cells but may serve a different role in the pathobiology of BCP-ALL.

cancer biology↗