Leukemia Propagating Cells Rebuild an Evolving Niche in Response to Therapy

Abstract

Residence of cancer-propagating cells (CPCs) within preferential microenvironmental niches has a major part in evading therapy. However, the nature of niches involved and the mechanisms protecting CPCs remain largely unknown. We addressed these issues in mouse transplantation models of acute lymphoblastic leukemia (ALL). When the engrafted leukemic cells substantially damaged adjacent microenvironment in the bone marrow (BM), after chemotherapy small foci of CPCs were retained, surrounded by sheaths of supporting cells that comprise a protective niche. We investigated patients' BM biopsies and found evidence of a similar process in patients receiving induction therapy. The efficacy of chemotherapy was enhanced by interfering with the niche formation or function. We therefore identified a therapy-induced niche that protects CPCs.

Neoplasms in the bone marrow niches: disturbance of the microecosystem

“…And, thus, a stochastic mechanism underlying these processes is proposed (Fig. 2c) in contrast to the findings and hypothesis in other leukemias in which specifically niches support and protect resident leukemic cells [37,39].…”

“…In our own studies, we observed that leukemic cells localize and graft in the preferential microenvironment where metastatic tumor cells spread in BM, alter, and disrupt normal BM microenvironments [37].…”

“…Leukemic dissemination synchronously disrupts osteoblasts and vascular structures, which are the main components of normal endosteal and vascular niches [37]. The extent of alteration depends on leukemic cell engraftment level.…”

“…The extent of alteration depends on leukemic cell engraftment level. After these models are released from leukemic burden by chemotherapy, "normal" environmental structure could not be restored [37]. In B-ALL, the dissemination of leukemic cells within BM may mechanically squeeze and chemically disrupt or modify marrow tissues.…”

“…We reported that GDF15 mediates the interaction between a therapy-induced niche and its resident LSCs, thereby conferring chemoresistance to residual LSCs in B-ALL. Furthermore, interfering with GDF15 expression or function significantly enhances chemotherapy efficacy [37].…”