Consolidation Chemotherapy Prevents Relapse by Indirectly Regulating Bone Marrow Adipogenesis in Patients with Acute Myeloid Leukemia

Abstract

Background/Aims: Chemotherapy is still the main strategy used to prevent the relapse of acute myeloid leukaemia (AML). As the most abundant stromal component in bone marrow (BM), marrow adipocytes have been previously shown to promote leukaemogenesis. The present study was designed to further validate whether marrow adipocytes exert synergistic effects on strengthening chemotherapeutic efficacy and evaluate the underlying mechanism. Methods: A retrospective study of BM biopsies from 80 patients with AML in remission and 71 control subjects was applied to quantitatively analyse the marrow adipocyte volume. Toxicity tests were used to assess the effect of chemotherapy drugs on BM cells. The possible mechanisms by which chemotherapy regulated the reduced marrow adipocyte content were investigated using antibody neutralization experiments, with an emphasis on growth differentiation factor 15 (GDF15). Results: In our study, the marrow adipocyte content was obviously reduced in the AML- complete remission (CR) group compared with the control group (P<0.001). Moreover, patients with a reduced adipocyte content exhibited longer relapse-free survival (RFS) (P<0.001). We also confirmed that GDF15 was overexpressed in mononuclear cells (MNCs) after treatment with chemotherapy drugs and partially blocked mesenchymal stem cells (MSCs) adipogenesis. Intriguingly, this inhibitory effect on adipogenesis was rescued by treatment with a neutralizing anti-GDF15 antibody. Conclusion: Chemotherapy indirectly inhibited adipogenesis by promoting GDF15 secretion from BM MNCs, subsequently strengthening the efficacy of consolidation chemotherapy in patients with AML during CR.

Hematopoietic Stem Cell Niche During Homeostasis, Malignancy, and Bone Marrow Transplantation

“…Moreover, transient receptor potential vanilloid 4 mediates GDF15-induced remodeling of BM adipocytes (Yang et al, 2019). A recent study revealed that in patients with AML during complete remission, chemotherapy drugs indirectly blocked MSC adipogenesis, enhanced the efficacy of consolidated chemotherapy, and prevented relapse by promoting GDF15 secretion from BM mononuclear cells (Liu et al, 2018). In addition, AML cells inhibited BMAs, resulting in erythropoiesis deficiency; this effect was reversed by the administration of PPAR-γ agonists in vivo (Boyd et al, 2017).…”

Bone Marrow Adipocytes: The Enigmatic Components of the Hematopoietic Stem Cell Niche

“…Of note, recently, chemotherapy-induced inhibition of adipogenesis has been suggested as a read-out of consolidation chemotherapy efficiency in AML patients during complete remission. Chemotherapy inhibited adipogenesis by promoting growth differentiation factor 15 secretion from BM mononucleated cells, thereby preventing relapse in AML patients [161].…”

Bone Marrow Fat and Hematopoiesis

“…Almost at the same time, other researchers reported opposite findings—that a decrease in adipocyte volume in patients with complete remission from AML is closely related to long-term recurrence-free survival. Growth differentiation factor 15, which is secreted by marrow mononuclear cells in response to chemotherapy and partially blocks adipogenesis, may exert synergistic effects on strengthening chemotherapeutic efficacy and may be used in predicting good outcomes for patients with AML during complete remission ( 83 ). These observations suggest that AML interrupts adipogenesis in red bone marrow, leading to impaired myelo-erythroid maturation ( 84 ).…”