Mesenchymal cells recruited by leukemic cells in the bone marrow reduce sensitivity to chemotherapy.
Major finding: Mesenchymal cells recruited by leukemic cells in the bone marrow reduce sensitivity to chemotherapy.
Clinical relevance: This niche was recurrently found in biopsies of patients who did not achieve complete remission.
Impact: Inhibiting the formation of this early protective niche may increase the efficacy of antileukemic agents.
Relapse after therapy is thought to be caused by surviving cancer cells that evade therapy by residing in protective microenvironmental niches, but the nature of such niches and the mechanisms by which they protect cancer cells are not well understood. Duan and colleagues transplanted fluorescently labelled human acute lymphoblastic leukemia (ALL) cell lines into mice and found that as leukemic cells disseminated, they damaged normal vascular and endosteal microenvironments. Upon treatment with the first-line ALL therapies cytarabine and daunorubicin, a small number of leukemic cells persisted in the bone marrow in a dynamic niche that transitioned from nestin-positive mesenchymal stem cells to α-smooth muscle actin (α-SMA)-positive cells. The formation and modification of this nestin–α-SMA (NSM) niche was mediated by the leukemic cells themselves, which secreted the chemotactic factor CCL3 to recruit the mesenchymal cells and the growth factor TGFβ1 to induce α-SMA expression. The NSM niche, a recurrent pathogenic mechanism observed in murine syngeneic leukemia mouse models, mice engrafted with primary ALL samples, and bone marrow biopsies of patients with ALL, did not protect residual leukemic cells by physically blocking drug delivery or promoting quiescence, but instead conferred drug resistance by inducing the secretion and subsequent proteolytic activation of the stress protein growth differentiation factor 15 (GDF15). GDF15 neutralization reduced the number of residual cells and prolonged survival in response to cytarabine treatment, suggesting that the NSM niche could represent a therapeutic target. Importantly, formation of a GDF15-expressing NSM niche could be observed in most patients who did not respond or responded only partially to chemotherapy but was not observed in patients who achieved complete responses. Therapeutic strategies that prevent or disrupt formation of the NSM niche could therefore circumvent chemoresistance in ALL and potentiate the efficacy of ALL chemotherapy.