Microenvironmental remodeling as a parameter and prognostic factor of heterogeneous leukemogenesis in acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by clonal proliferation of stem cell-like blasts in bone marrow; however, their unique cellular interaction within the bone marrow microenvironment and its functional significance remain unclear. Here, we assessed the bone marrow microenvironment of AML patients and demonstrate that the leukemia stem cells induce a change in the transcriptional programming of the normal mesenchymal stromal cells. The modified leukemic niche alters the expressions of cross-talk molecules (i.e., CXCL-12 and Jagged-1) in mesenchymal stromal cells to provide a distinct cross-talk between normal and leukemia cells, selectively suppressing normal primitive hematopoietic cells while supporting leukemogenesis and chemoresistance. Of note, AML patients exhibited distinct heterogeneity in the alteration of mesenchymal stroma in bone marrow. The distinct pattern of stromal changes in leukemic bone marrow at initial diagnosis was associated with a heterogeneous post-treatment clinical course with respect to the maintenance of complete remission for 5-8 years and early or late relapse. Thus, remodeling of mesenchymal niche by leukemia cells is an intrinsic self-reinforcing process of leukemogenesis that can be a parameter for the heterogeneity in the clinical course of leukemia and hence serve as a potential prognostic factor.