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

Abstract

AbstractB-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, withBCR-ABL1-positive andTCF3-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.