Bone Marrow Niche-Derived Extracellular Matrix-Degrading Enzymes Influence the Progression of B-Cell Acute Lymphoblastic Leukemia

Interactions with the bone marrow microenvironment (BMM) influence the pathophysiology of hematological malignancies. Reciprocally, hematological malignancies remodel the BMM in order to render it more hospitable for malignant progression. Hypothesizing that different leukemias differentially remodel stroma cells in the BMM, we tested differences in the expression of various genes in sorted osteoblastic cells from mice with B-cell acute lymphoblastic (B-ALL), acute myeloid (AML) or chronic myeloid leukemia (CML) or control mice by microarray. This revealed a high expression of various proteases, especially matrix metalloproteinase-9 (MMP-9), in osteoblastic cells isolated from mice with B-ALL. MMP-9 had previously been shown to be produced by leukemia cells.To investigate the physiological relevance of BMM-derived MMP-9 for the progression of B-ALL, we employed the well-established retroviral transduction/transplantation model of BCR-ABL1-dependent B-ALL in MMP-9-deficient or wildtype mice. Deficiency of MMP-9 in the BMM prolonged the survival of mice with B-ALL compared to wildtype mice. Secondary transplantation of bone marrow from wildtype versus MMP-9 knockout (KO) mice with B-ALL led to a significant prolongation of survival of recipients of B-ALL bone marrow from MMP-9 KO mice, suggesting that leukemia-initiating cells are reduced in a MMP-9 KO BMM. In addition, we observed reduced invasion of B-ALL cells into different organs such as spleen, meninges, lungs and liver, ...
Source: Blood - Category: Hematology Authors: Tags: 618. Acute Lymphoblastic Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: ALL Risk Associated Genes and Leukemia Infiltration Source Type: research